NOVEL INHIBITORS OF ADENOSINE MONOPHOSPHATE DEAMINASE

Abstract: Novel diazepine derivatives which selectively inhibit adenosine monophosphate deaminase and methods of preparing these compounds are provided. These compounds are useful in treating certain conditions in vivo which may be ameliorated by increased local concentrations of adenosine.

Description: NOVEL INHIBITORS OF ADENOSINE MQNQPflQgpHATE EWNAgE Rglgtg Appl cations This application is a continuation-in-part of serial number 08/012,841 filed February 3, 1993. Field of the Invention This invention relates to adenosine monophosphate deaminase inhibitors and to novel diazepine analogs, specifically to 3-substituted 3, 6,7, 8-tetrahydroimidazo [4, 5- d]diazepine analogs having activity as adenosine monophosphate deaminase inhibitors. The invention also relates to the preparation and use of these and other adenosine monophosphate deaminase inhibitors in the treatment of cardiovascular, and cerebrovascular diseases, central nervous system diseases, seizures, inflammation, sepsis, septic shock, endotoxemia, cancer, malaria and other parasites, AIDS (acquired immune deficiency syndrome) , and other diseases and in the treatment of pain. Background and Introduction to the Invention The present invention is directed to novel compounds which may act to increase local adenosine levels. Adenosine has been reported to have cardioprotective and neuroprotective properties. However, adenosine has also been reported to exhibit negative inotropic, chronotropic and dromotropic effects and to cause coronary steal by preferentially dilating vessels in nonischemic regions after systemic administration. These side effects limits the therapeutic potential of adenosine and other adenosine receptor agonists. Thus, it would be advantageous to increase adenosine concentrations locally, i.e. at a target site within the target tissue so that the beneficial effects of adenosine could be provided and the toxic systemic effects minimized. Adenosine monophosphate (AMP) deaminase ("AMP deaminase" or "AMPDA" ) is a cytosolic enzyme which catalyzes the deamination of AMP to inosine monophosphate (IMP) . Adenosine production is reported to be especially enhanced during ischemia when oxygen deprivation leads to adenosine triphosphate (ATP) breakdown and elevated intracellular levels of AMP. Intracellular AMP is catabolized to either adenosine by 5 ' -nucleotidase or converted to IMP by AMP deaminase. Studies have shown that AMPDA is a major pathway for AMP metabolism in ischemic tissues. Thus inhibition of AMPDA will lead to increased adenosine levels in a site- and event- specific manner. Adenosine is metabolized either via phosphorylation of the 5 ' -hydroxyl by adenosine kinase ( "AK" ) to give AMP or via deamination by adenosine deaminase ("ADA") to give inosine. Factors that determine the predominate pathway include local adenosine concentrations, kinetic characteristics of ADA and AK, and ADA versus AK intracellular specific activity. Since physiological adenosine concentrations are <100 nM and since ADA has a 100-fold higher Km for adenosine (Km = ~ 50 μM) relative to that of AK (Km = 0.5 μM) , ADA may be a significant factor in adenosine metabolism only at high adenosine concentrations. The rapid breakdown of ATP during ischemia leads to elevated local adenosine levels. Consequently, if adenosine levels are raised 100 fold during ischemia, ADA may begin to become important in local adenosine metabolism. Chronic total inhibition of ADA has been reported to lead to severe immunodeficiency. Children that are genetically deficient in ADA lack T- and B-cell activity and therefore are prone to a wide variety of life-threatening infections and diseases. Irreversible inhibition of ADA by the potent inhibitor, 2 ' -deoxycoformycin, has been reported to lead to a loss in B- and T-cell function and overall immunodeficiency. Although ADA deficiency and ADA inhibition leads to immunodeficiency, these studies have not found higher plasma adenosine levels. Gruber, U. S. patent 4,912,092, discloses (claim 38) "a method for enhancing the extracellular concentration of adenosine in tissue having an undesired region of decreased blood flow comprising the prophylactic administration of an adenosine monophosphate deaminase inhibitor." Four coformycin analogs have been reported to show activity as AMPDA inhibitors. The 5 ' -phosphorylated analogs of coformycin and deoxycoformycin have been reported to be potent inhibitors of rabbit muscle AMPDA (< 1 nM) . These compounds, however, are not expected to be useful .in vivo since they would not be bioavailable in cells due to the presence of the highly charged phosphate group. Secondly, dephosphorylation in vivo, which is a common and rapid metabolic pathway for other 5 ' -monophosphate nucleotides and other organophosphates in general would produce coformycin and deoxycoformycin respectively. Coformycin and deoxycoformycin are very potent inhibitors of ADA (<0.2 nM) but are significantly weaker AMPDA inhibitors (1000 nM) . Kinetic studies on the inhibition of ADA with coformycin and deoxycoformycin have shown that these compounds are tight binding inhibitors that result in irreversible inhibition of ADA. Consequently, inhibition of AMPDA with these compounds would lead to complete inhibition of ADA. Other coformycin analogs that have been reported include the aglycon attached to a short oxygenated chain, (acyclocoformycin in Showalter, et al. , J. Med. Chem. 1983, 26, 1478-1482) . No special utility or potential utility was reported for these compounds. Summary of the Invention The present invention is directed towards novel compounds which are potent AMPDA inhibitors. In one aspect, the present invention is directed to certain novel compounds that inhibit AMPDA, to the preparation of these compounds and to the in vitro and in vivo AMPDA inhibitory activity of these compounds. Another aspect of the present invention is directed to the clinical use of AMPDA inhibitors as a method of treatment or prevention of diseases responsive to enhanced local adenosine levels and in diseases responsive to modulation of purine metabolism flux. Although we do not wish to be bound by this or any particular theory, we believe that the novel adenosine monophosphate deaminase ("AMPDA") inhibitors of the present invention will be useful in enhancing local concentrations of adenosine in tissues which may benefit from increased extracellular adenosine levels in a site- and event-specific manner (Gruber, U.S. patent 4,912,092) . In one aspect, we believe that these AMPDA inhibitors will be useful in increasing adenosine levels in ischemic tissues. We believe ischemic tissues would have higher AMP levels relative to non- ischemic tissues due to net ATP breakdown. Inhibition of AMPDA would result in higher adenosine levels in the ischemic tissue without a global effect since AMP levels would not be increased in normal tissues. For example, these compounds may be useful in increasing adenosine production in ischemic cardiac tissue and therefore, increasing local adenosine levels and providing protection against damage. Gruber, U.S. patent 4,912,092, described the use of AMP deaminase inhibitors for treating diseases benefited by increased extracellular adenosine. AICA riboside which after phosphorylation to ZMP is able to inhibit AMP deaminase. ZMP, however, is rapidly cleared by a variety of enzymes including nucleotidase and cannot penetrate the cell membrane. We have demonstrated the ability of cell penetrable molecules to directly inhibit AMP deaminase, some of which are also capable of inhibiting adenosine deaminase. These cell penetrable molecules and prodrugε thereof, which are not cleaved by nucleotidase, are active in a variety of models of human diseases some of which are described herein. Direct enzyme inhibitors of the present invention have the advantage of not requiring metabolic energy (such as ATP and PRPP) as is required by molecules that undergo phosphoribosylation or phosphorylation. This advantage is especially important in cells undergoing net ATP depletion due to a lack of oxygen or nutrients as occurs during ischemia including central nervous system or cardiac ischemia. Furthermore, these molecules are specific AMP deaminase and optionally mixed AMP and adenosine deaminase inhibitors. That is, they do not inhibit adenosine kinase, adenosine transport or bind adenosine receptors in the concentration ranges where they almost completely inhibit AMP deaminase. Without inhibiting other enzymes, they are less likely to cause undesired side effects. Among other factors, the present invention is based on our finding that the novel compounds of the present invention are useful as AMP deaminase inhibitors and act to elevate and prolong extracellular adenosine levels and thereby enhance the pharmacological benefits of adenosine locally. These compounds are especially useful for the treatment of conditions and disorders responsive to the inhibition of AMP deaminase, particularly cardiovascular disorders, including cardiac arrhythmias and especially conditions related to ischemia such as myocardial infarction, angina (stable and unstable) , percutaneous transluminal coronary angiography (PTCA) , congestive heart failure, atherosclerosis, and other thrombotic and embolic disorders. The compounds are also useful in treating or preventing disorders such as stroke, neurologic disorders such as pain, seizure, insomnia, anxiety, or psychosis, and other conditions benefited by enhanced adenosine levels (at a selected locus) including inflammation, arthritis, autoimmune disease, ulcers and irritable bowel syndrome. Further, the compounds of the present invention are especially useful in the treatment or prevention of septic shock, sepsis, SIRS (SIRS is defined in Critical Care Medicine, vol 20, page 864-874, 1992, as a condition with no other apparent cause characterized by two or more of the following states: 1) body temperature > 38 °C or less than 36 °C; 2) heart rate > 90 beats/minute; 3) tachypnea with >20 breaths/minute or pC02 < 32 torr; or 4) white blood cell count >12,000 or < 4,000 cells/mL or > 10% immature neutrophils. ) , pancreatitis, burns and endotoxemia. In ? addition these compounds are useful as muscle relaxants, in inducing sleep and in treating anxiety. The present invention is further directed to the prophylactic and affirmative treatment of pain. AMP deaminase and mixed AMP and adenosine deaminase inhibitors are useful in the treatment of acute and chronic pain apparently by their ability to raise adenosine concentrations and down-regulate pain transmission in the spinal cord. For example, AMP deaminase inhibitors are useful in the treatment or prevention of acute and chronic pain. Accordingly, the present invention is directed to novel compounds that may be used clinically to treat or prevent medical conditions where an increased local adenosine concentration or where changes of purine metabolism is beneficial, such as cancer, gout, AIDS, or infection with malaria or other parasites. Further, in one embodiment the present invention is directed at compounds which are specific inhibitors of AMPDA and which show little or no interaction with other enzymes. In another embodiment, the present invention is directed to compounds which are selective inhibitors for both AMPDA and adenosine deaminase. These compounds comprise novel 3-substituted- [3 , 6, 7, 8- tetrahydroimidazo [4, 5-d] 1,3]diazepine derivatives as specified below in formula 1. Also included in the scope of the present invention are prodrugs of the compounds of formula 1. Formula 1 Since these compounds may have asymmetric centers, the present invention is directed not only to racemic mixtures of these compounds, but to individual stereoisomers. The present invention also includes pharmaceutically acceptable and/or useful salts of the compounds of formula 1, including acid addition salts and basic salts. These salts may be formed by the addition of hydrobromic, hydrochloric, sulfuric and like acids or by the addition of carboxylic or sulfonic and like acids. The basic salts may be formed by treatment with a suitable base such as sodium or potassium hydroxide. Also included in the scope of the present invention are prodrugs of the compounds of formula 1. Definitions In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise. The term "aryl" refers aromatic groups which have ac least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted. Carbocyclic aryl groups are groups wherein the ring atoms on the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and polycyclic or fused compounds such as optionally substituted naphthyl groups. Heterocyclic aryl groups are groups having from 1 to 3 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms carbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen, and include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl, and the like, all optionally substituted. The term "biaryl" represents aryl groups containing more than one aromatic ring including both fused ring systems and aryl groups substituted with other aryl groups. The term "alicyclic" means compounds which combine the properties of aliphatic and cyclic compounds and include but are not limited to aromatic, cycloalkyl and bridged cycloalkyl compounds. The term "optionally substituted" or "substituted" includes groups substituted by one to four substituentε, independently selected from lower alkyl, lower aryl, lower aryloxy, aralkyl, perhaloakloxy, aralkoxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, amino, guanidino, tetrazolo, 3H-1,2,3 , 5-oxythiodiazolo, thiazolidine- // 2,4-diono, oxazolidin-2, 4-diono, halogen, hydroxy, lower alkoxy, lower alkylthio, carboxyalkyl, carboxyl, carboxamido, carboxamidoalkylaryl, carboxamidoaryl, aminocarboxamidoalkyl, cyano, and lower perhaloalkyl . The term "aralkyl" refers to an alkyl group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl, and the like, and may be optionally substituted. The term "lower" referred to herein in connection with organic radicals or compounds respectively defines such as with up to and including 10, preferably up to and including 6, and advantageously one or two carbon atoms. Such groups may be straight chain or branched. The terms "arylamino" (a) , and "aralkylamino" (b) , respectively, refer to the group -NRR' wherein respectively, (a) R is aryl and R' is hydrogen or aryl, and (b) R is aralkyl and R' is hydrogen or aralkyl. The term "alkyla ino" refers to -NRR' where R and R' are independently selected from hydrogen or lower alkyl. The term "carboxamide" or "carboxamido" refers to -CONR2 where each R is independently hydrogen or alkyl. The term "alkyl" refers to saturated aliphatic groups including straight-chain, branched chain and cyclic groups. The term "alkenyl" refers to unsaturated groups which contain at least one carbon-carbon double bond and includes straight-chain, branched-chain and cyclic groups. The term "alkynyl" refers to unsaturated groups which contain at least one carbon-carbon triple bond and includes straight-chain, branched-chain and cyclic groups. The term "alkylene" refers to a divalent straight chain or branched chain saturated aliphatic radical. The term "acyloxy" refers to the ester group -0-C(0)R. The term "thioacyloxy" refers to the thioester group -S- C(0)R. The term "alkylenylaryl" refers to an alkylene group substituted with an aryl group. "Lower alkylenylaryl" refers to such groups where alkylene is lower alkylene. The term "alkylenylamino" refers to the group -alk-NH- wherein alk is an alkylene group. The term "alkylenylaminoalkylene" refers to the group -alk-NH-alk- wherein each alk is an independently selected alkylene. "Lower alkylenylaminoalkylene" refers to groups where each alkylene group is lower alkylene. The term "alkylenylaminoaryl" refers to an alkylene group substituted with an arylamino group. In "lower alkenylaminoaryl" , the alkylene group is lower alkylene. The term "alkylenyloxyaryl" refers to an alkylene group substituted with an aryloxy group. In "lower alkylenyloxyaryl", the alkylene group is lower alkylene. The term "alkylenylacylamino" refers to the group -alk-NH- (COR) - wherein alk is alkylene and R is lower alkyl. In "lower alkylenylacylamino", the alkylene group is lower alkylene. The term "alkylenyloxyalkylenylaryl" refers to an alkylene group substituted with an aralkyloxy group. "Lower 93 alkylenyloxyalkylenylaryl" refers to such groups where the alkylene group is lower alkylene. The term "alkylenylacylaminoalkylene refers to the group -alk-NH- (COR)-alk- where each alk is an independently selected alkylene group. In "lower alkylenylacylaminoalkylene" the alkylene groups are lower alkylene. The term "alkenyloxy" refers to the group -alk-O- wherein alk is an alkylene group. The term "alkoxyalkyl" refers to the group -alk-O-alk- wherein each alk is an independently selected alkylene group. In "lower alkoxyalkyl", each alkylene is lower alkylene. The term "alkylenethio" refers to the group -alk-S- wherein alk is alkylene group. The term "alkylthioalkyl" refers to the group -alk-S-alk- wherein each alk is an independently selected alkylene group. In "lower alkylthioalkyl" each alkylene is lower alkylene. The term "alkylcarboxamidoalkyl" refers to the group -alk-C(O)N(R)-alk- wherein each alk is an independently selected alkylene group and R is lower alkyl. In "lower alkylcarboxamidoalkyl", each alkylene is lower alkylene. The term "alkylcarboxamidoalkylaryl" refers to the group -alki-C(0)-NH-alk2 (Ar)- wherein alki and alk2 are independently selected alkylene groups and alk2 is substituted with an aryl group, Ar. In "lower alkylcarboxamidoalkylaryl", each alkylene is lower alkylene. The term "heteroalicyclic" refers to an alicyclic group having 1 to 5 heteroatoms selected from nitrogen, sulfur, ) phosphorus and oxygen. The term "aminocarboxamidoalkyl" refers to the group -NH-C (0) -N(R) -R wherein each R is an independently selected alkyl group. "Lower aminocaboxamidoalkyl" refers to such groups wherein each R is lower alkyl. The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group. The term "CONH-amino acid" refers to a carbonyl bound to the N-terminus of an amino acid. The term "coformycin aglycone" refers to 3',6',7',8'- tetrahydroimidazo[4 ' , 5' -d] [1' , 3 ' ]diazepin-8-ol. The term "prodrug" as used herein refers to any compound that when administered to a biological system generates the "drug" substance either as a result of spontaneous chemical reaction(s) or by enzyme catalyzed or metabolic reaction(s) . Reference is made to various prodrugs such as acyl esters, carbonates, and urethanes, included herein. The groups illustrated are exemplary, not exhaustive and one skilled in the art could prepare other known varieties of prodrugs. Such prodrugs of the compounds of formula 1, fall within the scope of the present invention. The term "pharmaceutically acceptable salt" includes salts of compounds of formula 1 derived from the combination of a compound of this invention and an organic or inorganic acid or base. The compounds of formula 1 are useful in both free base and salt form. In practice the use of salt form amounts to use of base form; both forms are within the scope of the present invention. Detailed Description of the Invention Novel Diazepine Compounds Preferred compounds of the present invention are adenosine monophosphate deaminase inhibitors of the following formula (1) . X wherein Y is -C(K)- or nitrogen; K is hydrogen, halogen, azido, or amino; G is hydrogen, lower alkyl, or amino; Z is azido, hydroxy, thio, lower acyloxy, or lower thioacyloxy; Z' is hydrogen or lower alkyl; J is hydrogen or lower alkyl; B is a straight or branched divalent group selected from lower alkylene, lower alkylenylaryl, lower alkylenylamino, lower alkylenylaminoalkylene.. lower alkylenylaminoaryl, lower alkylenyloxyaryl, lower alkylenylacylamino, lower alkylenyloxyalkyenylaryl, lower alkylenylacylaminoalkylene, lower alkyleneoxy, lower alkoxyalkyl, lower alkylenethio, lower alkylthioalkyl, lower alkynyl or lower alkenyl, alkylcarboxamidoalkyl, alkylcarboxamidoalkylaryl, hydroxylated lower alkylene, halogenated lower alkylene, halogenated lower alkylenylaryl, alkylenetetrazolo, alkylene-3H-l,2 ,3 , 5- oxythiodiazolo, alkylenethiazolidine-2-, 4-diono, alkyleneoxazolidin-2, 4-diono or is a direct link; A is a divalent group selected from a straight or branched alicyclic group, a straight or branched heteroalicyclic group, aryl group or heteroaryl group, all optionally substituted with substituents independently selected from lower alkyl, lower aryl, lower aryloxy, aralkyl, perhaloalkoxy, aralkoxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, amino, guanidino, halogen, hydroxy, lower alkoxy, lower alkylthio, carboxyalkyl, carboxyl, carboxamido, carboxamidoalkylaryl, carboxamidoaryl, aminocarboxamidoalkyl, cyano, lower perhaloalkyl, or is a direct link; X is hydrogen, lower alkyl, lower alkoxy, halogen, hydroxy, acyloxy, thio, amino, azido, cyano, carboxyl, carboxyalkyl, carboxyaryl, carboxyaralkyl, tetrazolo, 3H-1, 2,3,5- oxythiodiazolo, thiazolidine-2-, 4-diono, oxazolidin-2, 4-diono, carboxamido, carboxarnidoalkyl, carboxamidoaralkyl, carboxamidoaryl, guanidino, -PO3EE' , or C(W)C02E(COQ) ; E and E' are independently selected from hydrogen, lower alkyl, aryl or aralkyl; W is hydrogen, lower alkyl, halogenated lower alkyl, carboxyalkyl, carboxyaralkyl, or halogen; / Q is lower alkyl, lower alkoxy, aralkoxy, lower alkylthio, alkylamino, hydroxy, amino, arylamino, aralkylamino or aryloxy; and pharmaceutically acceptable salts thereof; with the proviso that (a) when B is a direct link, then A is not substituted tetrahydrofuran or substituted cyclopentylene; (b) when B is lower alkoxyalkyl and A is a direct link, then X is not hydroxy; and (c) when B is methylene and A is a direct link, then X is not hydrogen and (d) when B is methylene, X is hydrogen then A is not phenyl, (e) A and B cannot both be direct links. Preferred Compounds of Formula 1 Suitable alkyl include groups having from one to about twenty carbon atoms. Suitable aryl groups include groups having from one to about twenty carbon atoms. Suitable aralkyl groups include having from two to about twenty-one carbon atoms. Suitable acyloxy and thioacyloxy groups include groups having from two to about twenty carbon atoms. Suitable alkylene groups include groups having from one to about twenty carbon atoms. Suitable alicylic groups include groups having three to about twenty carbon atoms. Suitable heteroalicyclic groups include groups having from two to about twenty carbon atoms and from one to five heteroatoms, preferably independently selected from nitrogen, oxygen, phosphorous and sulfur. Preferred are compounds of formula 1 wherein: B is a divalent straight or branched lower alkylene, straight or branched lower alkylenylaryl, or a direct link; A is a divalent group selected from a straight or branched alicyclic group; a straight or branched heteroalicyclic group; aryl; or heteroaryl; all optionally substituted with substituents independently selected from amino, halogen, hydroxy, cyano, lower alkyl, lower perhaloalkyl, lower alkoxy, lower aryl, lower aryloxy, aralkyl, aralkoxy, and heteroaryl; or is a direct link; and X is hydrogen, carboxyl, carboxyalkyl, carboxyaryl, carboxyaralkyl, tetrazolo, 3H- 1, 2, 3 , 5-oxythiodiazolo, thiazolidine-2-, 4-diono, oxazolidin- 2,4-diono, or C (W)CO2E (COQ) ; where E and E' are independently selected from hydrogen, lower alkyl, aryl or aralkyl; W is hydrogen or lower alkyl; Q is lower alkoxy, aralkylamino, alkylamino, hydroxy, amino, arylamino or aryloxy. More preferred are compounds wherein: (a) X is hydrogen and A is a direct link; (b) X is hydrogen and A is aryl; (c) X is hydrogen and A is alicyclic; (d) A is a direct link and X is carboxyl, carboxyalkyl, carboxyaryl, carboxyaralkyl, tetrazolo, 3H-1,2,3,5- oxythiodiazolo, thiazolidine-2-, 4-diono, oxazolidin-2, 4-diono; (e) A is a direct link, and X is C (W)CO2E (COQ) where E and E' are independently selected from hydrogen, lower alkyl, aryl or aralkyl; W is hydrogen or lower alkyl; and Q is lower alkoxy, / aralkylamino, alkylamino, hydroxy, amino, arylamino, aralkylamino or aryloxy; or (f) A is not a direct link and X is carboxyl, carboxyalkyl, carboxyaryl, carboxyaralkyl, tetrazolo, 3H-1,2,3,5- oxythiodiazolo, thiazolidine-2-, 4-diono, oxazolidin-2, 4-diono. Preferred are compounds where Y is -C(-K)-. Preferred K groups include hydrogen. Preferred are compounds where G is hydrogen or methyl. Preferred are compounds where Z is hydroxy or azido and Z' is hydrogen. Preferred are compounds where Z is hydroxy and Z' is lower alkyl of one to three carbons. Preferred are compounds where J is hydrogen. Preferred are compounds where B is straight or branched lower alkylene, lower alkylenylaryl or a direct link. Preferred are compounds where A is a divalent group selected from a straight or branched alicyclic group, a straight or branched heteroalicyclic group, aryl or heteroaryl, all optionally substituted with substituents independently selected from amino, halogen, hydroxy, cyano, lower alkyl, lower alkoxy, lower aryl, lower aryloxy, aralkyl, perhaloakloxy, aralkoxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroaralkoxy or is a direct link. Preferred are compounds where X is hydrogen, carboxyl, carboxyalkyl, carboxyaryl, carboxyaralkyl, tetrazolo, 3H- 1, 2, 3 , 5-oxythiodiazolo, thiazolidine-2-, 4-diono, oxazolidin- 2,4-diono, or C (W)CO2E (COQ) ; where E and E' are independently selected from hydrogen, lower alkyl, aryl or aralkyl; W is hydrogen or lower alkyl; Q is lower alkoxy, aralkoxy, aralkylamino, alkylamino, hydroxy, amino, arylamino or aryloxy. A preferred group of compounds include compounds where Y is -C(-K)- and K is hydrogen; Z is hydroxy or azido and Z' is hydrogen and the carbon to which they are attached is of the R configuration. Another preferred group of compounds include compounds where Y is -C(-K)- and K is hydrogen; Z is hydroxy or azido; G and Z' are independently hydrogen or methyl; and J is hydrogen. More preferred are compounds where Y is -C(-K)- and K is hydrogen; Z is hydroxy or azido; G and Z' are independently hydrogen or methyl; J is hydrogen; B is straight or branched lower alkylene, straight or branched lower alkylenylaryl, or a direct link. Another more preferred group of compounds comprises those compounds where Y is -C(-K)- and K is hydrogen; Z is hydroxy or azido; G and Z' are independently hydrogen or methyl; J is hydrogen; A is a divalent group selected from a straight or branched alicyclic group, a straight or branched heteroalicyclic group, aryl, or heteroaryl, all optionally substituted with subεtituents independently selected from amino, halogen, hydroxy, cyano, lower alkyl, lower perhaloalkyl, lower alkoxy, lower aryl, lower aryloxy, aralkyl, aralkoxy, and heteroaryl; or A is a direct link. An additional group of more preferred compounds are compounds where Y is -C(-K)- and K is hydrogen; Z is hydroxy or azido, G and Z' are independently hydrogen or methyl; J is hydrogen; X is hydrogen, carboxyl, carboxyalkyl, carboxyaryl, carboxyaralkyl, tetrazolo, 3H-1,2, 3 , 5-oxythiodiazolo, thiazolidine-2-, 4-diono, oxazolidin-2, 4-diono, or C (W)C02E(COQ) ; where E and E' are independently selected from hydrogen, lower alkyl, aryl or aralkyl; W is hydrogen or lower alkyl; Q is lower alkoxy, aralkoxy, aralkylamino, alkylamino, hydroxy, amino, arylamino or aryloxy. A further group of more preferred compounds are compounds where Y is -C(-K)- and K is hydrogen; Z is hydroxy or azido, G and Z' are independently hydrogen or methyl; J is hydrogen; B is straight or branched lower alkylene, straight or branched lower alkylenylaryl, or a direct link; A is a divalent group selected from a straight or branched alicyclic group, a straight or branched heteroalicyclic group, aryl, or heteroaryl, all optionally substituted with substituents independently selected from amino, halogen, hydroxy, cyano, lower alkyl, lower perhaloalkyl, lower alkoxy, lower aryl, lower aryloxy, aralkyl, aralkoxy, and heteroaryl; or A is a direct link; X is hydrogen, carboxyl, carboxyalkyl, carboxyaryl, carboxyaralkyl, tetrazolo, 3H-1,2,3,5- oxythiodiazolo, thiazolidine-2-, 4-diono, oxazolidin-2, 4-diono, or C (W)C02E(COQ) ; where E and E' are independently selected from hydrogen, lower alkyl, aryl or aralkyl; W is hydrogen or lower alkyl; Q is lower alkoxy, aralkoxy, aralkylamino, alkylamino, hydroxy, amino, arylamino or aryloxy. Especially preferred are those compounds wherein (a) X is hydrogen and A is a direct link; (b) X is hydrogen and A is aryl; (c) X is hydrogen and A is alicyclic; (d) A is a direct link and X is carboxyl, carboxyalkyl, carboxyaryl, carboxyaralkyl, tetrazolo, 3H-1, 2, 3 , 5-oxythiodiazolo, thiazolidine-2-, 4-diono, oxazolidin-2, 4-diono; (e) A is a direct link, and X is C (W)C02E(COQ) where E and E' are independently selected from hydrogen, lower alkyl, aryl or aralkyl; W is hydrogen or lower alkyl; Q is lower alkoxy, aralkoxy, alkylamino, hydroxy, amino, arylamino, aralkylamino or aryloxy; (f) A is not a direct link and X is carboxyl, carboxyalkyl, carboxyaryl, carboxyaralkyl, tetrazolo, 3H-1,2,3,5- oxythiodiazolo, thiazolidine-2-, 4-diono, oxazolidin-2, 4-diono; (g) B is methylene, A is 1, 2- [6, 6-dimethyl [3.1.1]bicyclohept- 2-methylene] and X is hydrogen; (h) A is cycloheptylene, B is a direct link and X is hydrogen; (i) B is -(CH2.4-, A is a direct link, X is -C (W)C02E(C0Q) where W is hydrogen or methyl, E is aralkyl and Q is hydroxy; (j) B is -(CH2)4~. A is a direct link, X is -C (W)CO2E (COQ) where W is hydrogen or methyl, E is hydroxy, and Q is aralkylamino; (k) B is 1,7- [3,7-dimethyloct-6-enylene] , A is a direct link and X is hydrogen; (1) B is -(CH2)2~» and A is 1,3-arylene and X is carboxyl; (m) B is -(CH2)2~ and A is optionally substituted naphthalene; (n) B is -(CH2)2~/ A is 1, 3- (2-methyl)phenylene and X is carboxyl; (o) B is -(CH2)2 _ < A is 1, 3-naphthylene and X is carboxyl; (p) B is -(CH2)2~» A is 1.3- (5-bromo)phenylene and X is carboxyl; (q) B is -(CH2)2~ is 2,4-thienyl and X is carboxyl; (r) B is 1, 5- (6-arylhexylene) and X is carboxyl; (s) B is 1, 5- (6-phenylhexylene) and X is carboxyl; (t) B is 1, 5- (6- (3-bromophenyl)hexylene) and X is carboxyl; (u) B is alkyl of four to ten carbons, A is a direct link and X is hydrogen; (v) B is heptyl, A is a direct link and X is hydrogen; or (w) B is lower alkylene of two to seven carbons, more preferably two to five and A is aryl, more preferably phenylene, particularly preferred are those compounds where A is 1,2-phenylene and X is methyl or where A is 1, 4-phenylene and X is propoxy. In the following examples of preferred compounds, carboxylic acids are carboxylic acids and derivatives thereof including lower alkyl and lower alkylaryl esters and the known carboxylic acid mimics: tetrazole, 3H-1,2, 3 , 5-oxathiadiazole, thiazolidine-2, 4-dione and oxazolidine-2, 4-dione. Examples of preferred compounds include, but are not limited to: Preferred are the following compounds: 3- (trans-3 ' , 7' -dimethyl-2' , 6' -octadienyl) coformycin aglycone, (3 'R) -3- (3 ' , 7 ' -dimethyloct-6' -enyl) coformycin aglycone, 3-cycloheptylcoformycin aglycone (compound Id) , 3-cyclohexylmethylcoformycin aglycone, 3-cycloheptylmethylcoformycin aglycone, (l'S,2'S,5'S)-3-(6' , 6' -dimethyl [3,1,1] -bicyclohept-2' - methyl) coformycin aglycone (compound le) , (1"R,2"S, 5"R) -3- (2 ' - (2"-isopropyl-5"-methylcyclohexyloxy) - ethyl) coformycin aglycone, 3- (naphth-2 ' -ylmethyl)coformycin aglycone, 3- (2 ' - (naphth-l"-yl) ethyl) coformycin aglycone, 3- (2 ' - (naphth-2"-yl) ethyl) coformycin aglycone, 3- (2 ' -phenylethyl) coformycin aglycone, 3- (2 ' - (2"-methylphenyl)ethyl) coformycin aglycone, 3- (6' -carboxyhexyl)coformycin aglycone, 3- (7' -carboxyheptyl) coformycin aglycone, 3-carboxyethylthioethylcoformycin aglycone, N- (3- (3' , 6' , 1 ' ,8'-tetrahydroimidazo[4' , 5' -d] - [1' , 3 ' ]diazepin- 8' -ol-3 ' -yDpropyl) -N-formyl-D-phenylalanine, N-(3-(3',6',7', 8'-tetrahydroimidazo[4' , 5' -d] - [1' , 3 ' Jdiazepin- 8' -ol-3 ' -yl)propyl) -N-formyl-L-phenylalanine, N- (4- (3 ' , 6' , 1 ' , 8' -tetrahydroimidazo[4 ' , 5' -d] - [1' , 3 ' .diazepin- 8' -ol-3 ' -yUbutyryl) -L-phenylalanine, 2-amino-3- (5 ' -carboxy-5' -carbobenzyloxypentyl) coformycin aglycone, 2-bromo-3- (5 ' -carboxy-5' -carbobenzyloxypentyl) coformycin aglycone, 3- (5' -carbox-N-benzylamido-5' -carboxypentyl) -5- methylcoformycin aglycone, 3- (5' -carbox-N-benzylamido-5' -carboxypentyl) -8- methylcoformycin aglycone, 3- (5' -carbox-N- (4"-chlorobenzyl)amido-5' - carboxypentyl) coformycin aglycone, 3- ( ' -carboxamido-5' -carboxyhexyl) coformycin aglycone, 3- (2 ' - (o-carboxyphenylthio)ethyl) coformycin aglycone, 3- (3 ' - (3"-carboxy-6"-methylphenyl)propyl) coformycin aglycone, 3- (3 ' - (2"-methoxy-5"-carboxyphenyl)propyl) coformycin aglycone, 3- (2 ' - (3"-carboxy-6"-propylphenyl) ethyl) coformycin aglycone, 3- (2 ' - (3"-carboxy-6"-hydroxymethylphenyl)ethyl)coformycin aglycone, 3- (2 ' - (3"-carboxyphenyl) ethyl) coformycin aglycone, 3- (3 ' - (2"-carboxy-3"-fluorophenyl)propyl)coformycin aglycone, 3- (3 ' - (2"-carboxythiophen-3"-yl)propyl) coformycin aglycone, 3- (2 ' - (2"-carboxythiophen-5"-yl)ethyl) coformycin aglycone, 3- (3 '- (2"-carboxynaphthyDpropyl)coformycin aglycone, 2-bromo-3- (2 ' - (3"-carboxynaphthyl) ethyl) coformycin aglycone, 2-amino-3- (2 ' - (3"-carboxynaphthyl) ethyl) coformycin aglycone, 2-amino-3- (2 ' - (3"-bromo-5"-carboxyphenyl) ethyl) coformycin aglycone, 2-bromo-3- (2 ' - (3"-bromo-5"-carboxyphenyl)ethyl) coformycin aglycone, 2-bromo-3- (5' -carboxy-6' - (3"-bromophenyl)hexyl)coformycin aglycone, 2-amino-3- (5 ' -carboxy-6' - (3"-bromophenyl)hexyl) coformycin aglycone, 3- [2' - (7"-carboxybenzopyran-5"-yl)ethyl] coformycin aglycone, 3- [2 ' - (6"-carboxybenzopyran-8"-yl)ethyl] coformycin aglycone, 3- [2 ' - (3"-carboxy-5" , 6" , 7" , 8"- tetrahydronaphthyl)ethyl] coformycin aglycone, 3- [2' - (3"-carboxy-5" , 7"-benzodioxolyl) ethyl] coformycin aglycone, 3- [2' - (6"-carboxy-2" , 3"-dihydrobenzofuran-4"-yl)ethyl] - coformycin aglycone, 3- [2 ' - (3"-carboxyindane) ethyl] coformycin aglycone, 3- [2 ' - (5"-carboxy-2" , 3"-dihydrobenzofuran-7"-yl) ethyl] - coformycin aglycone, 3- [2' - (6"-carboxybenzothiophen-4"-yl)ethyl] coformycin aglycone, 3- [2' - (6"-carboxybenzofuran-4"-yl)ethyl]coformycin aglycone, 3- [2' - (3"-carboxyanthracenyl)ethyl]coformycin aglycone, 3- [2'- (3"-carboxyacenaphthyleny1)ethyl] coformycin aglycone, 3- [2 '- (3"-carboxyphenanthrenyl)ethyl] coformycin aglycone, 3- (6' -carboxy-β' -carbobenzyloxyhexyl) coformycin aglycone, 3- (5' -carboxy-6' -carbobenzyloxyhexyl) coformycin aglycone, 3- (5' -carboxy-5' , 5 ' -dibenzylpentyl) coformycin aglycone, 3- (5' -carboxy-5' -fluoro-6' -phenylhexyl)coformycin aglycone, 3- (5' -carboxy-6' - (2"-chlorophenyl)hexyl)coformycin aglycone, 3- (5' -carboxy-6' - (2"-iodophenyl)hexyl) coformycin aglycone, 3- (5' -carboxy-6 ' - (2"-tolyl)hexyl) coformycin aglycone, 3- (5' -carboxy-6' - (2"-trifluoromethylphenyl)hexyl) coformycin aglycone, 3- (5' -carboxy-6'- (2"-ethoxyphenyl)hexyl) coformycin aglycone, 3- (5' -carboxy-6' - (2"-benzyloxyphenyl)hexyl) coformycin aglycone, 3- (5' -carboxy-6 ' - (2"-hydroxyphenyl)hexyl) coformycin aglycone, 3- (5' -carboxy-6 ' - (4"-fluorophenyl)hexyl) coformycin aglycone, 3- (5' -carboxy-5' - (4"-fluorophenoxypentyl)coformycin aglycone, 3- (5' -carboxy-5' -hydroxy-6' -phenylhexyl) coformycin aglycone, 3- (5' -carboxy-5' -phenoxypentyl) coformycin aglycone, 3- (5' -carboxy-5' - (4"-chlorophenoxypentyl) coformycin aglycone, 3- (5' -carboxy-5' -benzyloxypentyl) coformycin aglycone, 3- (5' -carboxy-5' - (4"-chlorobenzyloxy)pentyl) coformycin aglycone, 3- (5' -carboxy-5'- (3"-bromophenoxypentyl) coformycin aglycone, 3- (3 ' - (2"-bromo-4"-propoxyphenyl)propyl) coformycin aglycone, 3- (3 ' - (2"-chloro-4"-propoxyphenyl)propyl)coformycin aglycone, 3- [2' - (3"-Carboxy-6" , 8"-dichloronaphthyl)ethyl] coformycin aglycone, 3- [2' - (3"-Carboxy-6" , 8"-difluoronaphthyl)ethyl]coformycin aglycone, 3-[2'- (3"-Carboxy-6", 8"- ditrifluoromethylnaphthyl) ethyl] coformycin aglycone, 3- [2 ' - (3"-Carboxy-8"-chloronaphthyl)ethyl]coformycin aglycone, 3- [2' - (3"-Carboxy-8"-trifluoromethylnaphthyl)ethyl] coformycin aglycone, 3- [2' - (3"-Carboxy-8"-methylnaphthyl)ethyl]coformycin aglycone, 3- [2 ' - (3"-Carboxy-8"-fluoronaphthyl) ethyl] coformycin aglycone, 3- [2' - (3"-Carboxy-7"-chloronaphthyl) ethyl] coformycin aglycone, 3- [2' - (3"-Carboxy-7"-bromonaphthyl)ethyl]coformycin aglycone, 3- [2 ' - (3"-Carboxy-7"-trifluoromethylnaphthyl)ethyl]coformycin aglycone, 3- [2' - (3"-Carboxy-7"-methylnaphthyl)ethyl]coformycin aglycone, 3- [2 ' - (3"-Carboxy-7"-fluoronaphthyl) ethyl] coformycin aglycone, 3- [2 ' - (3"-Carboxy-7"-phenoxynaphthyl) ethyl] coformycin aglycone, 3- [2' - (3"-Carboxy-7"-phenylnaphthyl)ethyl] coformycin aglycone, 3- [2 ' - (3"-Carboxy-7"-ethylnaphthyl) ethyl] coformycin aglycone, 3- [2 ' - (3"-Carboxy-5"- (p- chlorophenoxy)naphthyl)ethyl]coformycin aglycone, 3- [2' - (3"-Carboxy-5"-phenoxynaphthyl) ethyl] coformycin aglycone, 3- [2 ' - (3"-Carboxy-5" , 6" , 7"-trifluoronaphthyl) ethyl] coformycin aglycone, 3- [2' - (3"-Carboxy-5" , 6"-difluoronaphthyl)ethyl] coformycin aglycone, 3- [2' - (3"-Carboxy-5",7"-difluoronaphthyl)ethyl]coformycin aglycone, 3- [2' - (3"-Carboxy-6"-bromo-7"- fluoromethylnaphthyl) ethyl] coformycin aglycone, 3- [2' - (3"-Carboxy-9"-methoxyphenanthrene) ethyl]coformycin aglycone and 3- [2 ' - (2"-Carboxy-4"-phenanthrene) ethyl] coformycin aglycone. More preferred are the following compounds: 3-heptylcoformycin aglycone (compound la) , 3-heptyl-8-methylcoformycin aglycone (compound lb) , 3- (4 ' -benzylcycloheptyl) coformycin aglycone, 3- (4' - (2 ' "-phenylethyl) cycloheptyl) coformycin aglycone, 3- (3 ' --benzylcycloheptyl) coformycin aglycone, 3- (3 ' - (2 ' "-phenylethyl)cycloheptyl) coformycin aglycone, 3- (3 ' -cyclohexylpropyl) coformycin aglycone, 3- (2 ' - (2"-ethoxynaphth-l"-yl) ethyl) coformycin aglycone, 3- (2' - (3"-ethoxynaphth-l"-yl) ethyl) coformycin aglycone, 3- (2 ' - (4"-ethoxynaphth-l"-yl) ethyl) coformycin aglycone, 3- (2' - (5"-ethoxynaphth-l"-yl)ethyl)coformycin aglycone, 3- (2 ' - (6"-ethoxynaphth-l"-yl) ethyl) coformycin aglycone, 3- (2 ' - (7"-ethoxynaphth-l"-yl) ethyl)coformycin aglycone, 3- (2'- (8"-ethoxynaphth-l"-yl)ethyl)coformycin aglycone, 3- (2' - (naphth-2"-yl) ethyl) coformycin aglycone, 3- (2' - (l"-ethoxynaphth-2"-yl) ethyl) coformycin aglycone, 3- (2 ' - (3"-ethoxynaphth-2"-yl)ethyl)coformycin aglycone, 3- (2' - (4"-ethoxynaphth-2"-yl)ethyl) coformycin aglycone, 3- (2 '- (5"-ethoxynaphth-2"-yl) ethyl) coformycin aglycone, 3- (2 ' - (6"-ethoxynaphth-2"-yl) ethyl) coformycin aglycone, 3- (2' - (7"-ethoxynaphth-2"-yl)ethyl)coformycin aglycone, 3- (2 ' - (8"-ethoxynaphth-2"-yl) ethyl)coformycin aglycone, 3- (2' - (2"-propoxynaphth-l"-yl) ethyl)coformycin aglycone, 3- (2'- (3"-propoxynaphth-l"-yl) ethyl)coformycin aglycone, 3- (2 ' - (4"-propoxynaphth-1"-yl) ethyl)coformycin aglycone, 3- (2 ' - (5"-propoxynaphth-l"-yl) ethyl) coformycin aglycone, 3- (2' - (6"-propoxynaphth-l"-yl) ethyl)coformycin aglycone, 3- (2' - (7"-propoxynaphth-l"-yl) ethyl)coformycin aglycone, 3- (2 '- (8"-propoxynaphth-l"-yl) ethyl) coformycin aglycone, 3- (2 ' - (1"-propoxynaphth-2"-yl) ethyl) coformycin aglycone, 3- (2' - (3"-propoxynaphth-2"-yl) ethyl)coformycin aglycone, 3- (2 ' - (4"-propoxynaphth-2"-yl) ethyl) coformycin aglycone, 3- (2 ' - (5"-propoxynaphth-2"-yl) ethyl) coformycin aglycone, 3- (2'- (6"-propoxynaphth-2"-yl) ethyl)coformycin aglycone, 3- (2 ' - (7"-propoxynaphth-2"-yl) ethyl) coformycin aglycone, 3- (2 ' - (8"-propoxynaphth-2"-yl) ethyl) coformycin aglycone, 3- (3 ' -phenylpropyl) coformycin aglycone, 3- (3 '- (2"-methylphenyl)propyl) coformycin aglycone (compound If), 5-methyl-3- (3 ' - (2"-methylphenyl)propyl)coformycin aglycone (compound lg) , 3- (3 ' -propylphenyl) -8-azido-3 ,6,7, 8-tetrahydroimidazo[4, 5- d] [1,3]diazepine (compound lh) , 3- (3 ' - (2"-trifluoromethylphenyDpropyl)coformycin aglycone, 3- (3 ' - (3"-methylthiophen-2"-yl)propyl) coformycin aglycone, 3- (3 '- (2"-chlorophenyDpropyl) coformycin aglycone, 3- (3 ' - (3"-chlorophenyDpropyl) coformycin aglycone, 3- (3' - (2"-bromophenyl)propyl) coformycin aglycone, 3- (3 ' - (3"-bromophenyl)propyl) coformycin aglycone, 3- (3 ' - (2"-ethoxyphenyl)propyl) coformycin aglycone, 3- (3 '- (3"-ethoxyphenyl)propyl) coformycin aglycone, 3- (3 ' - (4"-ethoxyphenyl)propyl)coformycin aglycone, 3- (3 ' - (2"-benzyloxyphenyl)propyl) coformycin aglycone, 3- (3 ' - (3"-benzyloxyphenyl)propyl) coformycin aglycone, 3- (3 ' - (4"-trifluoromethoxyphenyDpropyl) coformycin aglycone, 3- (3 '- (4"-butoxyphenyl)propyl) coformycin aglycone, 3- (3 ' - (4"-isopropylphenyl)propyl) coformycin aglycone, 3- (3 ' - (4"-propylphenyl)propyl) coformycin aglycone, 3- (3 ' - (biphenyl-4"-yl)propyl)coformycin aglycone, 3- (3' - (2" , "-dimethylphenyl)propyl)coformycin aglycone, 3- (3 ' - (2" , 4" , 6"-trimethylphenyl)propyl) coformycin aglycone, 3- (3 ' - (2"-hydroxyphenyl)propyl)coformycin aglycone, 3- (3 ' - (4"-hydroxyphenyl)propyl) coformycin aglycone. 3/ 3- (5 ' -carboxypentyl) coformycin aglycone, 3- (5' - (tetrazol-5"-yDpentyl) coformycin aglycone, 3- (5' -carbobenzyloxy-5' -carboxyhexyl) coformycin aglycone, 3- (5' -carboxy-6 ' -phenylhexyl) coformycin aglycone (compound lj), 3- (5' -carboxy-6' - (2"-bromophenyl)hexyl) coformycin aglycone, 3- (5' -carboxy-6' - (4"-bromophenyl)hexyl)coformycin aglycone, 3- (5' -carboxy-5' -carbobenzyloxypentyl) -5-methylcoformycin aglycone, 3- (5' -carboxy-5' -carbobenzyloxypentyl) -8-methylcoformycin aglycone, 3- (5' -carbox-N-benzylamido-5' -carboxypentyl) coformycin aglycone, 3- (5' -carbox-N- (3"-bromobenzyl)amido-5' - carboxypentyl) coformycin aglycone, 3- (5' -carbox-N- (3"-bromobenzyl)amido-5' -carboxypentyl) -5- methylcoformycin aglycone, 3- (5' -carbox-N- (3"-bromobenzyl)amido-5' -carboxypentyl) -8- methylcoformycin aglycone, 3- (5' -carbox-N-cyclohexylmethylamido-5' - carboxypentyl) coformycin aglycone, 3- (5' -carbox-N-benzylamido-5' -carboxyhexyl) coformycin aglycone (compound 11) , 3- (5' -carbox-N- (2"-phenethyl)amido-5' -carboxyhexyl) coformycin aglycone, 3- (5' -carbox-N-cyclohexylamido-5' -carboxyhexyl) coformycin aglycone, 3- (5' -carbox-N-cyclohexylmethylamido-5' - carboxyhexyl) coformycin aglycone, 3- (3 ' - (2"-fluoro-5"-carboxyphenyl)ethyl)coformycin aglycone, 3- (2 ' - (2"-methoxy-5"-carboxyphenyl) ethyl) coformycin aglycone, 3- (2' - (3"-carboxy-4"-methylphenyl)ethyl) coformycin aglycone, 3- (2 ' - (3"-carboxy-4"-fluorophenyl) ethyl)coformycin aglycone, 3- (2' - (3"-carboxy-5"-ethylphenyl) ethyl) coformycin aglycone, 3- (2 ' - (3"-carboxybiphen-5"-yl) ethyl) coformycin aglycone, 3- (2' - (3"-carboxy-6"-methylphenyl)ethyl) coformycin aglycone (compound lm) , 3- (2 ' - (6"-methyl-3"- (tetrazol-5' "-yDphenyl) ethyl)coformycin aglycone (compound In) , 3- (2' - (3"-carboxy-6"-ethylphenyl) ethyl) coformycin aglycone, 3- (2 ' - (2"-carboxythiophen-4"-yl) ethyl) coformycin aglycone (compound lo) , 3- (2 ' - (3"-carboxynaphthyl)ethyl) -5-methylcoformycin aglycone, 3- (2' - (3"-carboxynaphthyl)ethyl) -8-methylcoformycin aglycone, 3- (2 ' - (3"-bromo-5"-carboxyphenyl) ethyl) -5-methylcoformycin aglycone, 3- (2 ' - (3"-bromo-5"-carboxyphenyl) ethyl) -8-methylcoformycin aglycone, 3- (5' -carboxy-6' - (3"-bromophenyl)hexyl) -5-methylcoformycin aglycone, 3- (5 ' -carboxy-6' - (3"-bromophenyl)hexyl) -8-methylcoformycin aglycone, 3- [2'- (2"-chloro-5"-carboxyphenyl) ethyl] coformycin aglycone, 3-[2' - (2" , 3"-dichloro-5"-carboxyphenyl)ethyl]coformycin aglycone, 3- [2 ' - (2"-trifluoromethyl-5"-carboxyphenyl) ethyl] coformycin aglycone, 3- [2 ' - (3"-carboxy-5"-pentafluoroethylphenyl)ethyl] coformycin aglycone, 3- [2 ' - (3"-carboxy-6"-pentafluoroethylphenyl)ethyl] coformycin aglycone, 3- [2 ' - (2"-chloro-3 "-carboxyphenyD ethyl] coformycin aglycone, 3- [2 ' - (2"-fluoro-3"-carboxyphenyD ethyl] coformycin aglycone, 3- [2'- (2"-carboxythiophen-4-yl)ethyl]coformycin aglycone, 3- [2' - (2"-carboxyfuran-4-yl)ethyl] coformycin aglycone, 3- [2' - (3"-carboxy-5"-chloronaphthyl)ethyl] coformycin aglycone, 3- [2 ' - (3"-carboxy-5"-bromonaphthyl) ethyl] coformycin aglycone, 3- [2 ' - (3"-carboxy-5"-trifluoromethyl naphthyl)ethyl] coformycin aglycone, 3- [2' - (3"-carboxy-5"-methylnaphthyl)ethyl] coformycin aglycone, 3- [2' - (3"-carboxy-5"-fluoronaphthyl)ethyl]coformycin aglycone, 3- [2' - (3"-carboxy-6"-chloronaphthyl) ethyl] coformycin aglycone, 3- [2 ' - (3"-carboxy-6"-bromonaphthyl)ethyl] coformycin aglycone, 3- [2' - (3"-carboxy-6"-trifluoromethyl naphthyl)ethyl]coformycin aglycone, 3- [2' - (3"-carboxy-6"-methylnaphthyl)ethyl] coformycin aglycone, 3- [ 2 ' - (3"-carboxy-6"-fluoronaphthyl) ethyl] coformycin aglycone, 3- [2 ' - (3"-carboxy-2"-chloronaphthyl) ethyl] coformycin aglycone, 3- [2' - (3"-carboxy-2"-fluoronaphthyl)ethyl] coformycin aglycone, 3- (5' -benzyl-5' -carboxy-5' -carbobenzyloxypentyl) coformycin aglycone, 3- (5' -carboxy-5' -carbox-N-benzylamidopentyl) coformycin aglycone, 3- (5' -carboxy-5' -carbox-N-cyclohexylamidopentyl) coformycin aglycone, 3- (5' -carboxy-5' -carbox-N-hexylamidopentyl) coformycin aglycone, 3- (5' -carboxy-5' -carbox-N- (4"-chlorobenzyl)amidopentyl) - coformycin aglycone. Most preferred are the following compounds: (3'S)-3-(3',7' -dimethyloct-6' -enyl) coformycin aglycone (compound lc) , 3- (3 '- (4"-propoxyphenyl)propyl) coformycin aglycone (compound li) , 3- (5' -carboxy-5' -carbobenzyloxypentyl)coformycin aglycone (compound Ik) , 3- (2' - (3"-carboxynaphthyl)ethyl)coformycin aglycone (compound lp) , 3- (2' - (3"-bromo-5"-carboxyphenyDethyl) coformycin aglycone (compound lq) , 3- (5' -carboxy-6' - (3"-bromophenyl)hexyl) coformycin aglycone (compound lr) . Synthesis of Preferred Compounds Preparation of Compounds of Formula 1 The synthesis of compounds of the present invention can be viewed as consisting of the following steps: (1) preparation of the heterocycle, (2) preparation of the electrophile, (3) coupling of the electrophile and the heterocycle, (4) reduction of 8-keto intermediate, if required, and (5) modification of the coupled molecule, if required. Each step is discussed below. The key transformation in this preparation, the coupling step, is shown below, as is the numbering system of the coformycin aglycone. (1) Preparation of the heterocycle The heterocycle, compound 2, is preferably prepared by the method of Chan, et al., J " . Org. Chem . 1982, 47, 3457-3464, with the alteration that the final intermediate is treated with triethylamine in CH2CI2 to generate the non-DMSO solvate freebase. The final step of this procedure may employ lower alkyl ortho esters, for example (EtO)3CCH3, to produce compounds of formula 2 where G is lower alkyl, for example methyl (as shown by Showalter, et al . , J. Med. Chem . 1983, 26, 1478-1482) . Compounds of formula 2 where Y is nitrogen may be prepared by a modification of the route of Acevedo, et al. , J " . Org. Chem . 1986, 51 , 1050-1058. By starting with an appropriate alkyl azide, a precursor to compound 2 may be obtained where R is a suitable protecting group such as benzyl (removable under Pd(OH) 2 catalyzed hydrogenation) . Alternatively, for compounds where R is B-A-M, this procedure constitutes a synthesis of compounds of formula 4. i DMFDMA H2 , Rainey Ni An intermediate step in the method of Chan, et al . , J. Org. Chem . 1982, 47 , 3457-3464 can be modified to employ nitro lower alkaneε and the latter steps modified as shown below to provide compounds of formula 2 where J is lower alkyl. Compounds of formula 2 where G iε oxygen may be obtained by substituting p-nitrophenyl chloroformate for GC(OEt) 3 and then hydrogenation can provide the desired heterocycle as has been εhown by the method of Hosmane, et al. , Nucleosides & Nucleotides 1991, 10, 1693-1706. A compound of the formula 2 where the absolute configuration at C8 is R may be obtained by the method of Truong and Rapoport J. Org. Chem . 1993, 58, 6090-6096, starting with L-methionine methyl ester to provide a protected form of 2 shown below. 2) Preparation of the Electrophile One method for the production of electrophile 3, shown below, involves treatment of an active hydrogen compound MH (where M is carboxyimidazole, carboxypyrazole, carboxypyrrole, HPO3R2, HC(W) (CO2R) (COQ) , optionally subεtituted phenolε or thiophenols, substituted mercaptans and dialkylamineε, and where W iε alkyl, halogen or carboxyalkyl) with a base, preferably NaH or K2CO3 , in a polar aprotic solvent (such as DMF or DMSO) or with an amine in an alcohol (such as ethanol) , and with a precursor electrophile (where L and L' are independently selected leaving groups, preferably both bromine, or L is a leaving group and L' is some group, preferably protected hydroxyl, which can be later modified to a leaving group, such as bromide or mesylate) . 1. Base MH L^ ^A N M 2. B L' Further, the generalized preparation of precurεors of the type MH are illustrated below. Typically, the active hydrogen compound is deprotonated by a suitable base, preferably sodium hydride and the reεulting anion alkylated with an appropriate derivative. ,C0 2 R 1. NaH, DMF C0 2 R < R 0 2 C- C0 2 R 2. C1C0 2 R w C0 2 R An alternative preparation of electrophile 3, from the corresponding alcohol, is shown below. Treatment, for example, with mesyl chloride and triethylamine in methylene chloride provideε the meεylate. If deεired, the mesyl group may be exchanged with bromide by treatment with tetrabutylammonium bromide. Alternatively, treatment of the alcohol with CBr4 , PPΪ13 and imidazole provides the bromide directly. NEt . CH .C1- Bu 4 N Br CBr , PPh 3 , Imidazole g r ^ A preparation of the alkoxy or alkylthio part of substituent B in compound 3 iε εhown below. Coupling of the precurεor alcohol with either an additional alcohol or thiol in the preεence of triphenylphosphine and diethyl azodicarboxylate (DEAD) gives the desired product. S' OH PPh 3 , DEAD Q M PX X A" K A An alternate method, shown below, iε to treat the alcohol with paraformaldehyde and HCl to produce the chloromethyl ether. HCl , CH-.C 1-. HO^ A, : — m m. CL ,0^ A„ R para <f=ormal . ,d_e>h . y . d . e CH 2 * R" M When M in compound 3 is azido , it may be prepared as εhown below for the ethyl derivative . TBnMcn NaN 3 i , BAF TBDMS ° ^ - βr ^ TBD SC^^ MsQ 2 . MsCl When εubεtituent A in compound 3 is cyclopropane and M is an eεter, the compound may be prepared by treatment of an olefin with ethyl diazoacetate in the preεence of a catalyεt, preferably Rh2(OAc) , aε shown below. When subεtituent A in compound 3 is a direct bond and B is a branched alkyl unit with the branching groups R' and R" being optionally H, lower alkyl or arylalkyl, preferably α to a carboxylate group, it may be prepared as outlined below. Stepwiεe alkylation of an appropriate ester or lactone using a base, such as lithium diisopropylamide, and an appropriate alkyl bromide, followed by a second alkylation gives the desired product. / / Αl(0R) 3 /AKOR) 3 Alternatively, when subεtituent A in compound 3 iε a direct bond and B iε a branched alkyl unit with a branching group being optionally aryloxy or hydroxy preferably α to a carboxylate group, it may be prepared as outlined below where in the case of the hydroxy branch the TBDMS ether is converted to the final hydroxy form using TBAF after coupling the electrophile to the heterocycle. The sequence below can also be applied if the branch is a fluorine atom when a fluorine iε substituted for the TBDMSoxy group . Compound 3 where A is optionally substituted aryl may be prepared as below starting from the appropriate aromatic precursor; where L is a leaving group, preferably iodide, bromide or trifluoromethylsulfonate. Treatment with propargyl alcohol in the presence of diethylamine with palladium catalyst produces a compound which in turn is hydrogenated and then converted to the final bromide or meεylate. The method iε applicable to the synthesis of isomerε where M iε on other positions of the ring and when the ring is optionally heterocyclic . The side chain can be lengthened by substituting terminal alkyne alcohols longer than propargyl alcohol. An alternate preparation of propylphenyl electrophiles iε shown in the following equation. By εubjecting a cinnamic acid to LiAlH4 reduction followed by hydrogenation if neceεsary and finally mesylation, the desired electrophile may be obtained. The electrophile in which the alkyl sidechain is εhorter by one carbon may be prepared aε εhown below. Treatment of the εtarting material with the palladium coupling conditions using allyltributylstannane as the nucleophile produces the adduct which is ozonized and reduced with sodium borohydride to the alcohol which may be converted into the appropriate leaving group. Alternatively, the ethyl sidechain may be incorporated by substituting vmyltributylstannane for allyltributylstannane which provides a vinyl derivative. This after hydroboration and oxidation gives an alcohol which after conversion to a leaving group L provideε the desired compound as shown below. An aryl group can be substituted with a phenyl ring using phenylboronic acid and palladium catalysis as in the following example with further elaboration providing the desired electrophile. Subεtituted naphthaleneε can be prepared by a known method which is illustrated in the following scheme. Thus, starting from a benzaldehyde, subεtituted carboxynaphthyl electrophiles may be prepared. MeONa An alternate preparation of an aryl containing electrophile involves reducing an iodobenzoic acid to the aldehyde, vinylation and then lithiation followed by ethyl chloroformate quench. Elaboration aε before would provide the desired electrophile. y^ A variation on this scheme is shown below and requires a bromobenzaldehyde to be methoxycarbonylated before elaboration of the formyl group into the bromoethyl sidechain as before. Vinylation of a bromophenylacetate and oxidation of the double bond can provide an aldehyde which is further modified to a bromoalkylphenylacetic acid ester as an electrophile. NaBH 4 as before A hydroxymethyl substituted aryl electrophile may be obtained from bromination of a toluate on the methyl group followed by displacement of the bromide with hydroxide and protection of the resulting alcohol as a TBDMS ether. Further elaboration as previouεly described provides the desired electrophile. as before Some other alternately substituted arylester electrophiles may be obtained aε shown below. Rearrangement of a phenylallyl ether provides a 2-allyl substituted phenol which after modification as before provides a TBDMS protected hydroxyethyl sidechain. The phenol is converted to a triflate and vinylated or allylated as before. Hydrogenation gives an ethyl or propyl sidechain. TBDMS deprotection and conversion to a bromide by previouεly described conditions provides the desired electrophiles. y* as before R = vinyl or allyl R = ethyl or propyl Construction of electrophiles where εubεtituent A is a heteroaryl may also be accomplished beginning with εubεtituted furan or thiophene (X' being O or S reεpectively) . The alcohol iε protected, preferably aε t-butyldimethylεilyl ether, using standard methods and the product iε deprotonated with n-butyllithium and then treated with a suitable chloroformate to give the carboalkoxy substituted heterocycle. Deεilylation and cqnverεion to the bromide by previously described conditions provides the desired electrophile. Imidazole One furanyl starting material (X' = 0) may be prepared as 4f below. Reaction of 2-furaldehyde with methoxymethyltriphenylphoεphonium bromide and n-butyllithium provideε a vinyl ether which after hydrolysis and NaBH4 reduction provides the desired alcohol. 3. NaBH 4 A 1, 2-cis-substituted cyclohexyl electrophile may be obtained as εhown below. cis-Cyclohexane dimethanol can be oxidized to a lactone which after reduction to a lactol undergoes coupling to form an acrylate. Hydrogenation and conversion to the bromide provides the desired electrophile. Another cyclohexyl containing electrophile may be obtained as εhown below. The trans-1, 4-cyclohexane dimethanol is converted to the monobromide in the usual manner and the remaining hydroxymethyl oxidized to an acid which after f esterif ication provides the desired electrophile . A method to make tetrazole containing electrophiles iε εhown below. Treatment of tetrazole with a baεe, preferably NaH, and trimethylsilylethoxymethylchloride (SEM-Cl) forms the protected tetrazole, which may be deprotonated at C5 with t- BuLi in a THF/DMPU εolvent εyεtem. Addition of the electrophile provideε the deεired adduct. An example of an alternate preparation of a tetrazole containing electrophile iε shown below. Coupling of a carboxylic acid with 3-aminopropionitrile followed by reaction with TMSN 3 and hydrolysis provides a tetrazole which can be protected and functionalized as before to give the desired electrophile. (3) Coupling of the electrophile and the heterocycle. Coupling of the appropriate heterocycle and electrophile is the next stage of the εynthesiε of compoundε of formula 1. Aε shown below, treatment of compound 2, the heterocycle, with a suitable base, such as sodium hydride or cesium carbonate, in a suitable polar aprotic solvent, such as DMF, followed by the addition of sodium iodide and the electrophile 3 where L is a suitable leaving group, preferably bromide or mesylate, provides 4, an intermediate for the preparation of compound 1. (4) Reduction of the C-8 ketone. The C-8 ketone is preferably reduced after coupling the heterocycle and the electrophile. The reduction may be performed preferably with NaBH4 in a mixture of methanol and methylene chloride to provide the desired alcohol. (5) Modification of the coupled molecule. The coupled molecule may require further elaboration to provide desired compoundε of formula 1, either before or after the reduction. The detailε of εuch modificationε are deεcribed below. Compounds of formula 1 where Z ' is lower alkyl may be obtained as shown below. Protection of N-6 in the adduct is accomplished by deprotonation and alkylation with SEM-Cl. Alkyllithium or alkylmagnesium halide addition to the ketone inserts the Z' group. The synthesis of the desired molecule is completed by desilylation with TBAF. Compound 1 where X is amino may be prepared by Pd/C catalyzed hydrogenation of the compound where X is azido and the resultant amine converted to a guanidino function by treatment with aminoiminomethanesulfonic acid as shown below. Compound 1 where X is OH or SH may be prepared by treatment of 4 where M is O-acyl or S-acyl, preferably acetate, with a hydrolytic agent, such as an alkoxide, preferably sodium methoxide in methanol. J^ " A MeONa, MeOH ^ " y B" " XAC (X = O or S;) *~ ' ~ B XH SΎ Compound 1 where X is CO2H is obtained by alkaline ester hydrolysis, preferably with aqueous NaOH, or by hydrogenolysis of a suitable benzyl (R = Bn) ester. r^ A NaOH or H 2 .. Pd/C r* A β' C0 2 R ^ X β' V C0 2 H Compound 1 where X is C (W) (CO2R) (COQ) , where W is H and Q iε OH, may be obtained by hydrolysis of the tricarboalkoxy- methyl precurεor with εuitable base, such as aqueous NaOH. ς NaOH j S X B X C(C0 2 R) 3 *" N B ^CH(C0 2 R)(C0 2 H) Compound 1 where X iε C (W) (CO2H) (COQ) may be obtained by alkaline hydrolysis of an alkyl ester or hydrogenolysis of the appropriate benzyl ester. -f A NaOH or H 2 , Pd/C _J" A B C(W)C0 2 R(COQ) - B" C(W)C0 2 H(COQ) Compound 1 where X is C(W) (C02H)2 may be obtained preferably by hydrogenolysiε of a dibenzyl eεter (R = Bn) aε εhown below. J " H 2 , Pd/C j S A ^ X B Aχ C(W)(C0 2 R) 2 - B' "C(W)(C0 2 H) 2 Compound 1 where X iε C(W) (CO2R) (COQ), where Q iε OR', SR' or NR'2, may be obtained from the eεter or amide forming reaction of the appropriate carboxylic acid with HOR' , HSR' or HNR'2 in the presence of a suitable coupling reagent, preferably diphenylphosphorylazide (DPPA) and triethylamine aε εhown below. \ A, DPPA, NEt 3 j J^ A B C(W)C0 2 R(C0 2 H) *- ^β C(W)C0 2 R(COQ) QH (Q = OR', SR', NR' 2 ) Compound 1 where X iε C(0)NH2 may be obtained by reaction of ammonia, with a εuitable ester in a suitable solvent, for example ethanol, as below. j J " NH 3 , Alcohol, Δ f -J " ^ X B" A "C0 2 R' ^ ^ X B /A C ( 0)NH 2 Compound 1 where X is C(0)NH-amino acid can be obtained by an amide forming reaction between a carboxylic acid and the amine terminus of an amino acid in the presence of suitable coupling reagents, εuch aε N-hydroxysuccinimide (NHS) and dicyclohexylcarbodiimide (DCC) as shown below. Compound 1 where X is a tetrazole can be obtained by treatment of an N-trimethylsilylethoxymethyl (SEM) protected tetrazole with fluoride, e.g.: CsF or tetrabutylammonium f fluoride (TBAF) , in DMF as shown below. Compound 1 where X is P(O) (OR)OH can be obtained by hydrolyεiε of a phosphonate diester with a suitable base, such as lithium methoxide in methanol or aqueous NaOH as shown below. Γ*N. A_ MeO i/MeOH r ^ A. Ei' PO a R 2 or N aOH aq ^ & P(0)(OR)Oh Compound 1 where X is PO3H2 can be obtained by hydrogenolysiε of a εuitable phoεphonate as shown below . A H 2- pd/c A B P0 3 R 2 - V B^ "P0 3 H 2 Compounds of formula 1 where Z is thiol or azide can be obtained as shown below. Treatment of the compound of formula 4 with thioacetic acid acetylates N-6. The C-8 hydroxy is then converted to a thioacetate or azide group after which methanolic ammonia provides the desired thiol or azide. When Z is azide it may be converted to compoundε where Z is amino by Pd/C catalyzed hydrogenation. trv B— A M SH or N 3 Compounds of formula 1 where Z iε an acyloxy or a thioester group may be obtained as εhown below. N-6 of the ketone iε protected by alkylation with benzyloxymethyl chloride (BOM-Cl) . Reduction of the ketone and converεion to an acetate or a thioacetate can be accomplished in the presence of PPh 3 , DEAD and acetic or thioacetic acid. Deprotection of N-6 by hydrogenolysiε provides the desired ester. The method deεcribed above for producing oxygen or εulfur derivativeε at C8 may be employed for the chiral εyntheεiε of analogε of compound 1. Preparation of εuitable, chiral precursors iε deεcribed above in "Preparation of the heterocycle." Treatment of the appropriate chiral alcohol with theεe conditions yields the chiral compound. The preparation of other chiral analogε can be achieved by applying methodε that are known to the art εtarting from the ketone, compound 4 where Z and Z' are = 0. For example, aεymmetric reduction of the 8-keto group to the chiral alcohol can be achieved with reagentε such as β- (3-pinanyl) -9- borabicyclo [3.3.l]nonane, chiral oxazaborolidines (CBS reduction) , other reagents, or enzymatically with a reductase. An alternate method for obtaining chiral compounds iε the reεolution of the C8 alcoholε enzymatically with a lipase. Furthermore, clasεical chemical methodε for reεolving εtereochemical mixtureε of alcoholε and thiols via phthalates and oxalates and their alkaloid saltε, or as a diastereomeric ester with a carboxylic acid such as camphoric acid, might be employed to generate the 8 R configuration. An alternate preparation of compounds of formula 1 which doeε not fall within the above deεcribed 4-εtep route iε εhown below. The known εtyrenyl substituted derivative shown below is εubjected to the alkylation procedure aε described above to give compounds which may be proceεεed in a manner deεcribed above to give compound 1. B— A B— A M M A modification of this route can be employed to prepare compounds of formula 1 where Y = C-K and K is Br, N 3 and NH 2 as shown below. Utility The adenosine monophosphate deaminaεe inhibitorε of the present invention may be used in the treatment of a variety of clinical situations where increasing local levels of adenosine are beneficial. In particular, these compoundε may be uεed in treating or preventing cardiovascular disorderε in which injury or dyεfunction iε cauεed by iεchemia and/or reperfuεion (following a period of ischemia) . These include (1) heart attack, a situation that arises from obstruction of one or more of the coronary arteries supplying blood to the heart muεcle, and which, if prolonged, leadε to irreverεible tiεsue damage, especially during or after surgery; (2) angina pectoris, a clinical condition in which the blood supply to the heart iε εufficient to meet the normal needε of the heart but insufficient when the needs of the heart increase (e.g. during exercise) , and/or when the blood supply becomes more limited (e.g. during coronary artery spasm); (3) unstable angina associated with pain at rest; and (4) silent ischemia. In each of these conditions, treatment with AMP deaminase inhibitors will increase local levels of adenosine. Blood flow to the ischemic tiεsue would be increased, tisεue damage reduced and function improved. Further, AMP deaminase inhibitors may also be used to treat or prevent congestive heart failure. In advanced coronary artery diseaεe or perεistent chest pain at rest, a number of clinical procedures are currently used to improve blood supply to the heart. These include percutaneous transluminal coronary angioplasty (PTCA) , percutaneous transluminal directional coronary atherectomy, laser atherectomy, intravascular stents and coronary artery bypass graft surgery. The compounds of the present invention will also be useful as adjunctive therapies to these techniqueε. Other clinical εettingε that involve iεchemia would also be ameliorated by agents effecting regional blood flow including organ transplantation, skin flap grafting and other reconstructive surgery, peripheral vascular diseaεe, endotoxemia, sepsis, toxic shock, hemorrhagic shock, pulmonary emboli, pulmonary injury secondary to burns (thermal injury) or septicemia, pulmonary hypertension, microembolization, glomerulonephritis or progressive glomerulosclerosis, atheroεcleroεiε, myocarditiε, vaεculitiε, cardiomyopathieε, intestinal ischemia, peripheral vascular disease, transient ischemic attacks, stroke and cardiopulmonary arrest. Adenosine monophosphate deaminase inhibitors will enhance protection afforded by preconditioning a tissue with a brief period of ischemia, before a more prolonged period of ischemia. Thrombolytic therapy has been limited by a number of factors including the resistance of some thrombi to lysis, delays in reperfusion, reperfusion injury, and reocclusion following succesεful thrombolysis. Theεe limitations are believed to be mediated, in part, by platelet aggregation and neutrophil activation and, since adenosine inhibits platelet aggregation in addition to its other effectε on preventing iεchemic injury, uεe of these AMP deaminase inhibitors may comprise a uεeful adjunctive therapy for thrombolytic therapy or for the treatment or prevention of thrombotic diεeaεes such as myocardial infarction, stroke, angina, deep vein thrombosiε, restenosiε, tranεient iεchemic attackε, and pulmonary emboluε . Adenoεine has been reported to be an endogenous modulator of inflammation by virtue of itε effectε on stimulated granulocyte function and on macrophage, lymphocyte and platelet function. AMP deaminase inhibitors, including the compounds of the present invention, may be useful in the ύ3 treatment of disorders of the immune system, in particular inflammatory disorderε and advantageouεly in the treatment of εepsis, εepticemia or endotoxemia. Further, these compounds may be used in treating conditions such aε arthritis, osteoarthritiε, vasculitis, autoimmune disease, adult respiratory distress syndrome (ARDS) , burns, pancreatitis, inflammatory bowel diseaεe, necrotizing enterocolitiε, chronic obεtructive pulmonary diεease (COPD) , psoriaεiε, conjunctivitiε, iridocyditis, myositis, cerebritis, meningitis, dermitis, renal inflammation, iεchemia, reperfuεion injury, peripheral vascular disease, atherosclerosiε, AIDS and other inflammatory diεorders. Stroke and central nervous system ("CNS") trauma are conditions where tisεue injury reεults from reduced blood supply to the CNS and are thus amenable to an intervention that provideε increaεed levels of adenosine to the compromised tissue. A significant component of the neurodegeneration resulting from stroke or CNS trauma or neurodegenerative diεeaεeε may be cauεed by increased excitatory amino acid release and senεitivity, which results in neurons being stimulated to death. As adenoεine haε been reported to inhibit excitatory amino acid releaεe (Burke and Nadler J. Neurochem.. 1988, 1:1541) and poεt-εynaptic reεponses, compounds of this invention may be used in stroke and trauma and may also be uεed in the treatment of conditions such as Parkinson's disease, AIDS, Amyotrophic Lateral Sclerosis, Huntington'ε chorea or in the treatment of diεorders related to the effects of aging such as Alzheimer's disease or in treating schizophrenia. AMP deaminase inhibitors may also be useful in reducing anxiety, as skeletal muscle relaxants and in preventing skeletal muscle εpasm. Adenosine has been proposed to serve as a natural anticonvulεant, thuε agents that enhance adenosine levels may be used in the treatment of seizure disorderε. AMP deaminaεe inhibitors may be used in the treatment of patientε prone to or inflicted with seizures or epilepsy or who might have chronic low or insufficient adenosine levels or might benefit from increased adenosine εuch aε those suffering from autism, cerebral palsy, insomnia or other neuropsychiatric symptoms. Other excitatory neuromuscular tiεεueε εuch as smooth muscle and cardiac muscle may be treated using these AMP deaminase inhibitors. In particular, these AMP deaminase inhibitors may be used to decrease contraction in smooth muscle such as in the gastrointestinal tract, or in vascular tisεue such as an artery to prevent vasospasm which may limit blood supply to a tisεue. Thuε, theεe AMP deaminaεe inhibitors may be used to treat or prevent conditions such as Buerger' s disease, Raynaud's diεeaεe, thromboangiitiε obliterans, angina, unstable angina, εilent iεchemia, or tranεient ischemic attacks. Other conditions suitable for such therapy include cardiac arrhythmiaε (including εupraventricular tachycardia), irritable bowel syndrome, and impotence. AMP deaminase inhibitorε find further utility in the treatment of chronic and acute pain when administered in a syεtemic or localized (e.g., intrathecal) fashion, for example in the treatment of acute pain including but not limited to pain caused by general trauma, surgical procedures or dental work. Oral administration may be useful in controlling chronic pain including but not limited to pain caused by arthritis, cancer, trigeminal neuralgia, multiple scleroεiε, neuropathieε such as those arising from diabetes and AIDS and in addition, lower back pain and phantom limb pain. In general, compounds of the present invention need to inhibit AMPDA with a Ki of about 500 μM or less. Preferably they inhibit AMPDA with a Ki of about 10 μM or less. These tests are run in a manner similar to those described in Example A using purified or semi-purified enzyme extracts. For certain indications compounds which are dual inhibitors of both AMP deaminase and ADA may be advantageous. Such compounds may have a synergistic activity due to inhibition of both enzymes and therefore would exhibit their desired therapeutic effect at lower doseε and lower percent inhibition of each enzyme. For example, inhibition of AMPDA increaεeε adenoεine concentration to a level where ADA becomeε important in adenosine metabolism, thus inhibition of both enzymes is synergistic. Also complete inhibition or nearly complete inhibition of either enzyme would not be necessary. Toxicities due to lack of functional enzyme have been reported for both AMPDA and ADA-deficient humans. Complete ADA deficiency results in severe combined immunodeficiency. Complete AMPDA deficiency is reported to result in mild muscle fatigue. Use of a compound which inhibits both AMPDA and ADA would give beneficial effects without complete inhibition of either enzyme and therefore the use of such compounds would not result in the toxicities reported for complete inhibition of either enzyme. Such compounds may be particularly suited for treatment of acute conditions. AMPDA inhibitors having low activity aε ADA inhibitorε may be particularly εuited for treatment of chronic conditionε. Selective AMP deaminaεe inhibitorε or mixed AMP deaminaεe and ADA inhibitorε will be uεeful in the treatment of infections, especially those caused by protozoa and worms. They will also be useful in combination with therapy which involves purine and/or pyrimidine metabolism. Such therapies include antivirals εuch aε acylovir, azidothymidine, dideoxyinosine, adenosine arabinoside, dideoxyadenosine, ribovirin and cancer chemotherapies such as 5-fluorouracil, azathiopyrine, dacarbazine, cytosine arabinoside, methotrexate, brendinin, tiazafurin, 2 ' -deoxycoformycin and 2 ' -deoxy-2-chloroadenosine. The drugs of the present invention will also be useful in immunosuppressive, e.g., organ transplant, therapy. Cancer cells and parasiteε, especially malaria, have special requirements for purines compared to mammalian cells. These εpecial needε for purines have resulted in research directed to the discovery of agentε which interfere with purine pathways. For example, methotrexate and 6- mercaptopurine for the treatment of cancer and allopurinol for the treatment of leischmania. Although we do not wish to be bound by this or any other theory, we believe that AMP deaminase inhibitors or mixed AMP deaminaεe and adenosine deaminase inhibitors will be useful for treating cancer and parasitic infections, especially malaria, by their ability to interrupt purine metabolism. We believe that by preventing AMP and adenosine deamination, the cancer cell or parasite will become starved for guanylates and become unviable. To asεiεt in understanding the present inventions and especially their properties and utilities, the results of a series of experiments are also included. These experiments demonstrated that a number of compounds of formula 1 were potent inhibitors of AMP deaminase. Moreover, we have shown that many of these compounds are specific inhibitors of AMP deaminase and inhibit adenosine deaminase (ADA) much less εtrongly. In other experimental modelε, the ability of selected AMP deaminase inhibitors to inhibit neutrophil adherence to cardiomyocyte cellε, an inflammatory reεponse mediated at the cellular level was evaluated (Example C) . Neutrophil adhesion, migration into the extravascular space and secretion of cytotoxic products such as oxygen free radicals and proteaseε aε well as physical obstruction of capillaries by activated neutrophils have been reported as mechanismε by which neutrophilε contribute to myocardial tiεεue injury, especially after ischemic tissue is perfused with oxygenated blood. We have demonstrated the ability of these compounds to reduce damage resulting from ischemia and/or reperfusion in an experimental ischemic heart model as shown in Examples D, G and I and in an experimental ischemic brain model aε shown in Example F. Examples F and I demonstrate the ability of these compoundε to reduce infarct size. We have also shown the ability of these compounds to inhibit thrombosiε as shown in Example H. Further we have also demonstrated the ability of these compounds to prevent or treat neurologic disorders such as seizures as shown in Example E. Formulations Compoundε of the invention are administered to the affected tissue at the rate of from 0.3 to 30 nmole/min/kg, preferably from 1 to 10 nmole/min/kg. Such rates are easily maintained when these compounds are intravenouεly adminiεtered aε diεcuεεed below. When other methods are used (e.g., oral administration) , use of time-release preparationε to control the rate of releaεe of the active ingredient may be preferred. These compounds are given in a dose of about 0.1 mg/kg/dose to about 30 mg/kg/doεe, preferably from about 0.3 mg/kg/doεe to about 10 mg/kg/doεe. For the purpoεeε of thiε invention, the compounds may be adminiεtered by a variety of meanε including orally, parenterally, by inhalation spray, topically, or rectally in f formulationε containing pharmaceutically acceptable carrierε, adjuvants and vehicles. The term parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques. Intraarterial and intravenous injection as used herein includes administration through catheterε. Preferred for certain indicationε are methodε of administration which allow rapid access to the tissue or organ being treated, such as intravenous injections for the treatment of myocardial infarction. When an organ outside a body is being treated, perfuεion is preferred. Pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration. When uεed for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powderε or granuleε, emulεionε, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agentε and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluentε, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such aε maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, εuch as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monoεtearate or glyceryl distearate alone or with a wax may be employed. Formulations for oral use may be also presented as hard gelatin capsuleε where the active ingredient iε mixed with an inert εolid diluent, for example calcium phoεphate or kaolin, or aε εoft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil. Aqueous suεpenεionε of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspenεionε. Such excipientε include a εuεpending agent, εuch as sodium carboxymethylcellulose, methylcelluloεe, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents εuch aε a naturally occurring phoεphatide (e.g., lecithin), a condenεation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate) , a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., 7/ heptadecaethyleneoxycetanol) , a condenεation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate) . The aqueous suspension may also contain one or more preservative such aε ethyl or n-propyl p-hydroxy- benzoate, one or more coloring agent, one or more flavoring agent and one or more εweetening agent, such as sucrose or saccharin. Oil εuεpenεionε may be formulated by εuspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, seεame oil or coconut oil, or in a mineral oil εuch aε liquid paraffin. The oral εuspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. Disperεible powderε and granules of the invention suitable for preparation of an aqueouε εuεpenεion by the addition of water provide the active ingredient in admixture with a diεpersing or wetting agent, a suεpending agent, and one or more preservatives. Suitable disperεing or wetting agentε and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatideε, εuch aε soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such aε sorbitan monooleate, and condensation products of these partial esterε with ethylene oxide, εuch aε polyoxyethylene εorbitan monooleate. The emulεion may alεo contain εweetening and flavoring agents. Syrups and elixirs may be formulated with εweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent. The pharmaceutical compositions of the invention may be in the form of a εterile injectable preparation, εuch as a sterile injectable aqueous or oleaginous suεpension. This suspenεion may be formulated according to the known art uεing those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The εterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a εolution in 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and εolventε that may be employed are water, Ringer's solution and isotonic sodium chloride εolution. In addition, t sterile fixed oils may conventionally be employed as a εolvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acidε such as oleic acid may likewise be used in the preparation of injectables. The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-releaεe formulation intended for oral adminiεtration to humanε may contain 20 to 200 μmoleε of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions. It is preferred that the pharmaceutical composition be prepared which provides easily measurable amounts for administration. For example, an aqueous εolution intended for intravenouε infusion should contain from about 20 to about 50 μmoles of the active ingredient per milliliter of solution in order that infusion of a εuitable volume at a rate of about 30 ml/hr can occur. Aε noted above, formulationε of the preεent invention suitable for oral administration may be presented aε diεcrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granuleε; aε a εolution or a suspenεion in an aqueouε or non- aqueous liquid; or aε an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be adminiεtered as a bolus, electuary or paste. A tablet may be made by compresεion or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose) , lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, crosε-linked povidone, croεε-linked sodium carboxymethyl cellulose) surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or εcored and may be formulated so aε to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcelluloεe in varying proportionε to provide the deεired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach. Thiε iε particularly advantageouε with the compounds of formula 1 as such compounds are susceptible to acid hydrolysiε . Formulationε suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucroεe and acacia or tragacanth; paεtilles comprising the active ingredient in an inert basiε such as gelatin and glycerin, or sucroεe and acacia; and mouthwaεheε comprising the active ingredient in a suitable I liquid carrier. Formulations for rectal administration may be presented as a suppository with a suitable base compriεing for example cocoa butter or a εalicylate. Formulationε εuitable for vaginal administration may be presented as pesεarieε, tamponε, creamε, gelε, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate. Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, bufferε, bacterioεtatε and εoluteε which render the formulation iεotonic with the blood of the intended recipient; and aqueouε and non-aqueouε sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze- dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to uεe. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit doεage formulationε are thoεe containing a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, of an adenosine monophosphate deaminase inhibitor compound. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular diseaεe undergoing therapy, aε iε well understood by those skilled in the art. Examples of use of the method of the invention includes the following. it will be understood that theεe exampleε are exemplary and that the method of the invention iε not limited εolely to theεe exampleε. The method may be used following thrombolysis for coronary occluεion. The compound would be given aε a εterile injectable preparation with water or iεotonic sodium chloride as the solvent. The εolution can be adminiεtered intravenouεly or directly into the coronary artery at the time of left heart catheterization or into a carotid artery. The rate of adminiεtration could vary from 1 to 20 nmole/min/kg with, for example, an infusion volume of 30 ml/hr. Duration of therapy would typically be about 96 hours. Angina, early myocardial infarctε and other disorders where intravenous administration of drug may be preferable can be treated by using a sterile injectable preparation uεing the rateε discusεed above. Capεules comprising adenoεine monophosphate deaminase inhibitorε suitable for oral administration according to the methodε of the preεent invention may be prepared aε follows: (1) for a 10,000 capsule preparation: 1500 g of adenosine monophosphate deaminase inhibitor iε blended with other ingredientε (as described above) and filled into capsules which are suitable for administration depending on dose, from about 1 capsules per day to about 8 capsuleε per day (2 capεuleε per 6 hours) , to an adult human. The compounds of this invention and their preparation can be understood further by the examples which illustrate some of the procesεeε by which these compounds are prepared. These exampleε should not however be construed as εpecifically limiting the invention and variations of the invention, now known or later developed, are considered to fall within the εcope of the present invention as herein after claimed. EXAMPLES Example 1. Preparation of the Electrophile. 1.0 mmol of an active hydrogen compound was treated with 1.1 mmol of NaH in 4 L of DMF followed by addition of 1.5 mmol of the 1,ω-dibromoalkane. This mixture was stirred for 16 h. Extraction and chromatography provided the desired bromoalkyl electrophile. The following compounds were prepared in this manner: diethyl 2- (4 ' -bromobutyl) -2-methylmalonate as an oil, dibenzyl 2- (4' -bromobutyl) -2-methylmalonate as an oil, dimethyl 5-bromopentylphosphonate as an oil, dimethyl 6-bromohexylphosphonate aε an oil, dibenzyl 5-bromopentylphosphonate as an oil and dibenzyl 6-bromohexylphosphonate as an oil. Example 2. Preparation of 5, 5.5-Tricarbobenzyloxypentylbromide. A mixture of 1 mmol of dibenzylmalonate and 2.5 mmol of NaH in 3 mL DMF was stirred at 0 °C for 1 h and then 1.5 mmol of CBz-Cl waε added and εtirring continued for 1.5 h at 0 °C. Extraction and chromatography provided tricarbobenzyloxymethane aε an oil. A mixture of 1 mmol of thiε compound and 1.4 mmol of NaH in 10 mL of DMF waε stirred at 0 °C for 1 h and then 2 mmol of 1, 5-dibromopentane and stirring continued for 16 h at 90 °C. Extraction and chromatography provided the title compound. Example 3. Alternate Preparation of the Electrophile. A mixture of 1 mmol of the active hydrogen compound, 2 mmol of K2CO3 and 1.5 mmol of 1, 2-dibromoethane in 1 mL of DMSO was εtirred for 4 h at rt . Extraction and chromatography provided the deεired bromoalkyl electrophile. The following compoundε were prepared in this manner: 2- (p-carbomethoxyphenoxy)bromoethane as an oil and 2- (p-carbomethoxyphenylthio)bromoethane aε an oil. Example 4 . Preparation of Methyl 2- (2 ' -Bromoethylmercapto) -3- iεopropylbenzoate . To a εolution of 1.0 mmol 2-isopropylthiophenol and 2.2 mmol TMEDA in 2 mL cyclohexane was added 2.2 mmol n-BuLi. Then after stirring 24 h it was added to εolid C02 and stirred for 16 h when extraction and chromatography provided 2- mercapto-3-iεopropylbenzoic acid. The methyl eεter of thiε waε treated as in example 3 to provide the title compound. Example 5. Preparation of l-Bromo-3-mercaptoacetomethoχypropane. A solution of 1 mmol ethyl mercapatoacetate, 1.25 mmol 1, 3-dibromopropane and 1 mmol triethylamine in 2 mL ethanol waε stirred for 16 h at rt. Extraction and chromatography provided the title compound aε an oil. Example 6. Preparation of n-Prooyl Bromoethylmercaptopropionate. A εolution of 1.0 mmol of n-propyl 3-mercaptopropionate, 3.0 mmol of diiεopropylethylamine and 3.0 mmol of 1,3- dibromopropane in 2 mL of toluene waε refluxed for 3 h. Extraction and chromatography provided the title compound aε an oil. The following compound waε prepared in the same manner: ethyl 1- (3 ' -bromopropyl) -2-piρeridinecarboxylate aε an oil. Example 7 . Preparation of l-Bromo-2- (3 ' -carbomethoxyphenoxy) ethane. A solution of 1 mmol methyl m-hydroxybenzoate, 2.3 mmol triphenylphosphine and 2.3 mmol 2-bromoethanol in 17 mL of THF was cooled to 0 °C and 2.3 mmol diethyl azodicarboxylate (DEAD) was added. The mixture was stirred at rt for 11 h. Chromatography provided the title compound as an oil. Example 8. Preparation of Dimethyl N- (3-Bromopropyl) iminodiacetate. A mixture of 1 mmol iminodiacetic acid di ethylester hydrochloride εalt, 5 mmol N,N-diisopropyl-ethylamine and 3 mmol 1, 3-dibromopropane in 2 mL toluene was stirred at 90 °C for 16 h and then chromatographed to provide the title compound as an oil . Example 9. Preparation of Arylalkylbromideε and Arylalkylmeεylateε . A mixture of 1.0 mmol of aryl iodide (or triflate or bromide), 0.1 mmol of Pd(PPh3 ) 2CI2, 0.05 mmol of Cul, 2.0 mmol of alkyne alcohol, and 4 mL base (diethylamine or triethylamine) was εtirred until complete by tic (3-72 h) . Chromatographic purification provided the arylalkyne alcohol. A mixture of 1.0 mmol of the arylalkyne, 0.1 mmol of 10 % Pd/C in 5 mL EtOAc was hydrogenated and then filtered and concentrated to provide the arylalkanol . 9/ A mixture of 1.0 mmol of the arylalkanol, 1.2 mmol of PPh3 , 1.2 mmol of CBr , and optionally 1.2 mmol of imidazole in 3 mL of CH2CI2 was stirred for 5 min. and then chromatographed to provide the title arylalkylbromide. Alternatively, 1.0 mmol of the arylalkanol was mixed with 1.5 mmol MεCl and 1.5 mmol triethylamine in CH2CI2 for 1 h and then extractive iεolation provided the title arylalkylmeεylate. The following compounds were prepared in this manner: 2- (3 ' -bromopropyl)toluene as an oil, 2- (3 ' -bromopropyl) trifluoromethylbenzene as an oil, 2- (3 ' -bromopropyl) -1, 5-dimethylbenzene as an oil, 2- (3 ' -bromopropyl) -1,4-dimethylbenzene as an oil, 2- (3 ' -bromopropyl)mesitylene aε an oil, 2- (3 ' -bromopropyl) -3-methylthiophene aε an oil, 3-(4' -propylphenyl)propane mesylate as an oil, 6- (2' -bromophenyl)hexyl mesylate as an oil, methyl 3- (3 ' -bromopropyl)benzoate as an oil, methyl 3- (3 ' -bromopropyl) -4-methoxybenzoate as an oil, methyl 2- (3 ' -bromopropyl)benzoate as an oil, methyl 2-fluoro-6- (3 ' -bromopropyl)benzoate as an oil, methyl 5- (3 ' -bromopropyl) furan-2-carboxylate as an oil, methyl 3- (3 ' -bromopropyl)thiophene-2-carboxylate as an oil, methyl 2- (3 ' -bromopropyl) -3-isopropylbenzoate as an oil, methyl 2- (3 ' -bromopropyl) -3-isopropyl-6-methylbenzoate as an oil, methyl 2- (3 ' -bromopropyl) -4-methylbenzoate as an oil, methyl 2- (3 ' -bromopropyl) -5-methylbenzoate as an oil and methyl 1- (3 ' -bromopropyl) -2-napthalene-2-carboxylate as an oil. Example 10. Preparation of N-Methyl- (3- (3 ' -bromopropyl) -4-methylphenyl) - carboxamide. A solution of 1.0 mmol of 3-iodo-4-methylbenzoic acid, 1.2 mmol of TsCl, and 25 mmol of Py waε εtirred for 3 h and then 5 mmol of methylamine hydrochloride was added and εtirring continued for 5 h. Chromatography provided N-methyl- (3-iodo-4-methylphenyl) carboxamide. Thiε compound waε coupled with propargyl alcohol, hydrogenated and converted to the title bromide aε an oil by methodε previouεly deεcribed. Example 11. Alternate Preparation of Arylpropyl mesylates. A solution of 1 mmol of a cinnamic acid in 2 mL THF waε added εlowly to 2 mL of a 1 M εolution of LiAlH4 in THF at 0 °C. After 2 h stirring at rt extractive isolation provided a residue which was optionally subjected to hydrogenation in methanol over 10 % Pd/C. Filtration and evaporation provided the arylpropyl alcohol and this was mesylated aε previouεly described. The following compounds were prepared in this manner: 3- (2 ' -chlorophenyDpropyl mesylate as an oil, 13 3- (3 ' -chlorophenyDpropyl mesylate as an oil, 3- (4 ' -chlorophenyDpropyl mesylate as an oil, 3- (2' -bromophenyl)propyl mesylate as an oil, 3- (3 ' -bromophenyl)propyl mesylate as an oil, 3- (4' -bromophenyl)propyl mesylate as an oil, 3- (2' -ethoxyphenyl)propyl mesylate as an oil, 3- (3 ' -ethoxyphenyl)propyl mesylate as an oil, 3- (4 ' -ethoxyphenyl)propyl mesylate aε an oil, 3- (4' -methoxyphenyl)propyl meεylate aε an oil, 3- (4 ' -trifluoromethoxyphenyDpropyl mesylate as an oil, 3- (4 ' -iεopropylphenyl)propyl meεylate aε an oil and 3- (biphenyl-4 ' -yl)propyl mesylate aε an oil. Example 12. Alternate Preparation of Alkoxyarylpropyl mesylates. A mixture of 1 mmol of a hydroxycinnamic acid, 2.1 mmol alkyl bromide (or iodide) and 2.1 mmol K2CO3 in 4 mL of DMF was heated at 80 °C for 6 h and then extractive isolation provided the alkyl alkoxycinnamate and this compound was reduced and mesylated as before to provide the title compound. The following compounds were prepared in this manner: 3- (2' -benzyloxyphenyl)propyl mesylate aε an oil, 3- (3 ' -benzyloxyphenyl)propyl mesylate as an oil, 3- (4' -benzyloxyphenyl)propyl mesylate as an oil, 3- (4' -propoxyphenyl)propyl mesylate as an oil and 3- (4' -butoxyphenyl)propyl mesylate as an oil. */ Example 13 . Preparation of Bromoethylthiophenyl Carboxylates. A solution of 1.0 mmol of hydroxyethylthiophene, 5.0 mmol imidazole, 0.1 mmol DMAP and 1.2 mmol TBDMSCl in 4 mL of DMF was stirred for 6 h. Extraction and chromatography provided the TBDMS ether. To a solution of 1.0 mmol of this thiophene in 2 mL of THF waε added 1.2 mmol of n-BuLi at -78°C. After 5 h an alkyl chloroformate was added. Extraction and chromatography provided an ester. A solution of 1.0 mmol of this ester and 1.5 mmol of TBAF in 2 mL of THF was stirred at 0°C for 12 h. Extraction and chromatography to provided a hydroxyethylthiophene which was converted to the title bromide by the previously described method. The following compoundε were prepared in this manner: benzyl 5- (2 ' -bromoethyl) thiophenyl-2-carboxylate as an oil and methyl 4- (2 ' -bromoethyl) thiophenyl-2-carboxylate as an oil. Example 14. Preparation of N- (3-Mesyloxypropyl) -N-formylphenylalanine Methyl Eεterε. To a mixture of 1 mmol of phenylalanine methyl eεter hydrochloride and 2 mmol of triethylamine in 1 mL of DMF at 0 °C waε added 2 mL of formic acid and 0.7 mL of acetic anhydride. After stirring for 16 h at rt, extractive isolation provided N-formylphenylalanine methyl ester. A mixture of 1 mmol of ethXis compound and 1.2 mmol of NaH in 10 mL DMF at 0 °C was stirred for 1 h and then 1.2 mmol of 3-t-butyldimethylεilyloxypropylbromide waε added and εtirring continued for 16 h at rt. Extraction and chromatography provided an adduct which after treatment with TBAF and then mesylation of the resultant alcohol by methods previously described provided the title compound. The following compounds were prepared in this manner: N- (3-meεyloxypropyl) -N-formyl-L-phenylalanine methyl ester as an oil and N- (3-Mesyloxypropyl)-N-formyl-D-phenylalanine methyl ester as an oil. Example 15. Preparation of Ethyl 2-Benzyl-6-mesyloxyhexanoateε. A solution of 1 mmol of caprolactone in 0.5 mL THF was added to a solution of LDA in 0.5 mL THF at -78 °C and this stirred for 2 h. Then a solution of 1.1 mmol of a benzylbromide in 0.14 mL DMPU was added to the above mixture and after stirring for 1 h at -15 °C, the 2-benzylcaprolactone was isolated by extraction and chromatography. A mixture of 1 mmol of this lactone and 1 mmol of Al(OEt)3 was refluxed in toluene for 14 h. Extraction and chromatograpy provided an ethyl 2-benzyl-6-hydroxyhexanoate which was converted to a title mesylate by previously deεcribed methods. The following compoundε were prepared in this manner: ethyl 2-benzyl-6-mesyloxyhexanoate as an oil, ethyl 2- (2' -bromobenzyl) -6-mesyloxyhexanoate as an oil, ethyl 2- (3 ' -bromobenzyl) -6-mesyloxyhexanoate as an oil and ethyl 2- (4 ' -bromobenzyl) -6-mesyloxyhexanoate as an oil. Example 16. Preparation of 2- (2 ' -Iεopropyl-5' -methylcvclohexyloxy)ethyl bromideε. A mixture of 1 mmol of a menthol and 1.1 mmol of NaH waε stirred in DMF for 1 h followed by the addition of 1.3 mmol bromoethyl-t-butyldimethylsilyl ether and εtirring at 60 °C for 16 h. Extraction and chromatography provided the adduct. Thiε adduct waε desilyated with TBAF and converted to the title bromide by previously deεcribed methodε. The following compoundε were prepared in this manner: (l'R, 2 'S, 5'R) -2- (2 ' -isopropyl-5' -methylcyclohexyloxy)ethyl bromide aε an oil and (l'S,2'R,5'S)-2-(2' -iεopropyl-5' -methylcyclohexyloxy)ethyl bromide as an oil. Example 17. Preparation of Ethyl 3-Bromo-4- (hvdroxymethvDbenzoate TBDMS ether. A mixture of 1.0 mmol of ethyl 3-bromo-4-methylbenzoate, 1.0 mmol NBS, and 0.02 mmol benzoyl peroxide in 5 mL CCI4 was refluxed for 4 h and then procesεed by filtration and chromatography to provide ethyl 3-bromo-4-bromomethylbenzoate as an oil . A mixture of 1.0 mmol of this compound in 3 mL of dioxane and 5.0 mmol of CaCθ3 in 6 mL of H2O was stirred for 12 h at 100 °C and then processed by chromatography to provide 3- bromo-4-hydroxymethylbenzoic acid as solid. Silylation of this compound was performed as previously described and esterification by standard conditions provided the title compound as an oil. Example 18. Preparation of Alkyl 3- (2'-bromoethyl)benzoates. A mixture of 1.0 mmol of an alkyl 3-bromobenzoate, 1.5 mmol allyltributyltin, and 0.1 mmol Pd(PPh3)4 in 4 mL DMF waε stirred at 90°C for 1-16 h and then chromatographed to provide an alkyl 3-allylbenzoate. Ozone was pasεed into a εolution of 1.0 mmol of thiε allyl derivative in 10 mL of MeOH at -78 °C until blue. Nitrogen degassing was followed by addition of 5 mmol of NaBH4 and after stirring for 1 h the mixture was processed by chromatography to provide an alkyl 3- (2'-hydroxyethyl)benzoate which was converted to the title compound by a previously described method. The following compounds were prepared in this manner: methyl 3- (2'-bromoethyl)benzoate as an oil, benzyl 3- (2' -bromoethyl) -4-methylbenzoate aε an oil, methyl 3- (2' -bromoethyl) -4-methylbenzoate aε an oil, ethyl 3- (2'-bromoethyl)-4-methylbenzoate as an oil, f methyl 3- (2 ' -bromoethyl) -4-methoxybenzoate as an oil, ethyl 3- (2 ' -bromoethyl) -4-fluorobenzoate as an oil and ethyl 3- (2' -bromoethyl) -4- (t-butyldimethylsilyloxymethyl) - benzoate as a deliquescent solid. Example 19. Preparation of Ethyl 3- (2' -bromoethyl) -5-bromobenzoate. A mixture of 1.0 mmol of the ethyl 3-allyl-5- bromobenzoate (prepared as previously described), 0.1 mmol of Ruθ2, 2.5 mmol of NaI04, 4 mL of CCI4, 6 mL of H2O and 4 mL of CH3CN waε εtirred for 15 min. Then it was extracted and treated with 1.0 mmol of NaBH4 in 2 mL of MeOH to produce an alcohol which was converted to the title bromide by a previouεly deεcribed method. Example 20. Preparation of Ethyl 3- (Bromomethyl)phenylacetate. A mixture of 1.0 mmol of ethyl 3-bromophenylacetate, 1.5 mmol of vinyltributyltin, and 0.1 mmol of Pd(PPt_3)4 in 4 mL DMF waε εtirred and heated at 90°C for 1-16 h. Chromatography provided ethyl 3-vinylphenylacetate. A solution of 1.0 mmol of this olefin, 0.2 mmol of Os04, 1.2 mmol of NMO, 3 mL of t-BuOH, 3 mL of H2O and 7 mL of THF was stirred for 3 h and then after the addition of 12.0 mmol of NaHC03, 15 mL of H20 and 3.0 mmol of NaIθ4 the mixture was εtirred for 45 min. Extraction and chromatography provided the aldehyde. A εolution of 1.0 mmol of this aldehyde and 1.0 mmol of NaBH4 in 2 mL of MeOH waε εtirred for 1 h. Chromatography provided ethyl 3- (2' -hydroxyethyl) -5-bromobenzoate aε an oil. This compound was converted to the title compound by a previouεly deεcribed method. Example 21. Preparation of 5-Subεtituted Ethyl 3- (2' -bromoethyl) - benzoateε. A mixture of 1.0 mmol of ethyl 3- (2 ' -hydroxyethyl) -5- bromobenzoate, 0.1 mmol of Pd(Ph3)4, 1.5 mmol of a phenylboronic acid or 1.5 mmol of a vinyltributyltin, 3.0 mmol of K2CO3, 3 mL of diglyme and 1 mL of H2O waε heated at 90 °C for 12 h. Chromatography provided a compound which waε converted to the title bromide by a previouεly described method. The following compoundε were prepared in thiε manner: ethyl 3- (2 ' -bromoethyl) -5-phenylbenzoate aε an oil and ethyl 3- (2 ' -bromoethyl) -5-ethylbenzoate aε an oil from hydrogenation of the 5-vinyl derivative. Example 22. Ethyl 2-methyl-5- (2 ' -bromoethyl)benzoate. A mixture of 1.0 mmol of 3-iodo-4-methylbenzoic acid and 1.2 mmol of NaBH4 in 4 mL of anhydrouε THF waε stirred for 30 min and then 0.5 mmol of iodine in 2.0 mL of THF at 5 °C was added. After stirring for 2 h the mixture was processed by extraction to provide 3-iodo-4-methylbenzyl alcohol. A mixture of 1.0 mmol of this alcohol and 5.0 mmol of Mnθ2 in 5 mL of CH2CI2 was stirred for 16 h at rt. Chromatography provided 3-iodo-4-methylbenzaldehyde. This aldehyde (lmmol) was added to a premixed solution of 1.5 mmol of methyl triphenylphosphonium bromide and 1.2 mmol of n-BuLi in 5 mL of THF at 0 °C and this mixture was stirred for 3-6 h at rt and then procesεed by extraction and chromatography to give 3-iodo-4-methylεtyrene. To a εolution of 1 mmol of thiε iodide in 4 mL of THF was added 1.2 mmol of BuLi and after stirring for 1 h at -78 °C, ethyl chloroformate was added. Extraction and chromatography provided ethyl 2-methyl-5-vinylbenzoate. 1.0 mmol of this styrene derivative in 4 mL of THF was treated with 2.0 mmol of 9-BBN in THF and after stirring for 30 h and cooling to 0°C, 4.0 mmol of 30 % hydrogen peroxide followed by 2.1 mmol of 3N NaOH was added. After stirring for 10 h the mixture waε processed by extraction and chromatography to provide ethyl 2-methyl-5- (2 ' - hydroxyethyl)benzoate. This alcohol waε converted by a previouεly deεcribed method to the title compound aε an oil. Example 23. Preparation of Methyl 2-Fluoro-5- (2'bromoethyl)benzoate. A mixture of 1.0 mmol of 3-bromo-4-fluorobenzaldehyde, 4 mL of DMF, 0.2 mL of triethylamine, 0.4 mL of MeOH and 0.05 mmol of Pd(PPh3)4 was heated at 90 °C at 40 pεi under CO atmoεphere for 16 h. Extraction and chromatography provided methyl 3-carbomethoxy-4-fluorobenzaldehyde. Thiε aldehyde was treated aε previouεly deεcribed to provide the title compound aε an oil. Example 24. Preparation of Methyl 4- (2 ' -Bromoethyl) -2-naohthoate. The compound 4-bromo-2-naphthoic acid waε prepared according to the method of Adcock and Wells, Aust . J. Chem. 1965, 18, 1351. It was converted to its methyl ester by standard methods. This naphthylbromide was crosε coupled with vinyl stannane, the resulting naphthylvinyl compound subjected to hydroboration/oxidation and the resulting alcohol converted to the title compound aε an oil all by previously described methods. Example 25. Preparation of 2-Bromomethyl-cis- (2' -carbomethoxyethyl) - cvclohexane. A mixture of 1 mmol of 1, 2-ciε-cyclohexane dimethanol, 10 mL of CH2CI2, 0.4 g of molecular sieves (4 angstroms) and 3.0 mmol of PCC was stirred for 3 h. Chromatography provided ciε- 1,2-hexahydrocoumaranone aε an oil. A εolution of 1.0 mmol of thiε cyclohexyllactone in 1 mL of toluene and 1.02 mmol of DIBALH at -78°C waε stirred for 2 9<X h. Extraction and chromatography provided a lactol as an oil 1 mMol of this lactol in 2 mL CH3CN was added to a premixed suεpenεion of 2.0 mmol of NaH and 3.0 mmol of carbomethoxymethyltriphenylphoεphonium bromide in 2 mL of CH3CN at 0 °C and then the mixture was stirred for 5 h at 80 °C. Extraction and chromatography provided methyl cis-(2'- hydroxymethylcyclohexyl) -2-acrylate as an oil. This ester was hydrogenated and converted to the title bromide aε an oil by previously described methods. Example 26. Preparation of Methyl trans-4-Bromomethylcvclohexane Carboxylate. 1, 4-tranε-cyclohexane dimethanol was converted to trans- 4-Bromomethylcyclohexane methanol by previouεly described methods. A solution of 1.0 mmol of this alcohol and 5.0 mmol of PDC in 10 mL of DMF was stirred at rt for 36 h. Extraction and chromatography provided a carboxylic acid which was converted to the title ester by a standard procedure. Example 27. Preparation of 4-Substituted Methyl 3- (2' -Bromoethyl) - benzoates. A mixture of 1.0 mmol of methyl 4-hydroxybenzoate, 2.0 mmol of allyl bromide, 5.0 mmol of K2CO3 in 2 mL of acetone waε εtirred for 16 h. Extraction provided methyl 4- allyloxybenzoate. A solution of 1.0 mmol of this allylether, 1.0 mmol of BC13 in 5 mL of chlorobenzene was stirred 6h at rt. Extraction provided 2-allyl-4-carbomethoxyphenol. This compound was subjected to ozonolysis and TBDMS ether formation by previously described methods to provide 2-(2'-t- butyldimethylsiloxyethyl) -4-carbomethoxyphenol. A solution of 1.0 mmol of this phenol, 6.0 mmol of triethylamine, and 2.4 mmol of Tf20 in 4 mL of THF was stirred at -78 °C for 1 h, then concentrated and dissolved in 4 mL of DMF. To this was added 0.15 mmol of Pd(PPh3 ) 2CI2 , 0.4 mmol of PPh3 , 8.0 mmol of LiCl, and 2 mmol of vinyl or allyl tributyltin and the mixture heated at 90°C for 14 h. Extraction and chromatography provided the methyl 4- subεtituted-3- (2 ' -t-butyldimethylsiloxyethyl)benzoate. After hydrogenation by a previously described method, a solution of 1.0 mmol of the resulting protected alcohol, 0.1 mmol of CSA in 1 mL of MeOH and 1 mL of CH2CI2 was stirred for 10 h. Extraction and chromatography provided an alcohol which was converted to the title bromide by a previously described method. The following compounds were prepared in thiε manner: methyl 3- (2' -bromoethyl) -4-ethylbenzoate aε an oil and methyl 3- (2' -bromoethyl) -4-propylbenzoate as an oil. Example 28. Preparation of l-Bromo-2- (2 ' -carboethoxycvclopropyl) ethane. Ethyl diazoacetate (1.3 mmol) was added over 18 hours to a solution of 1.0 mmol 4-bromo-l-butene and 2 mg dirhodium tetraacetate in 10 mL of CH2CI2. The solution waε concentrated, filtered through silica, and fractionally distilled to give the title compound as an oil. Example 29. Preparation of 5- (5' -Bromopentvl) -2-trimethvlsilvl- ethoxymethyltetrazole. To a suspension of 1.1 mmol NaH in 5 mL DMF at 0 °C was added a εolution of 1.0 mmol tetrazole in 2 mL DMF. After 30 min, trimethylεilylethoxymethylchloride waε added and the mixture stirred for 16 h. Extraction and chromatography provided trimethylsilylethoxymethyltetrazole as an oil. To a solution of 1.0 mmol of this tetrazole in 4 mL of THF and 4 mL of 1, 3-dimethyl-3 , 4, 5, 6-tetrahydro- 2 (lH)pyrimidinone at -78 °C was added 1.5 mL of 1.7 M t- butyllithium in pentane. After 5 min, 5 mmol of 1,5- dibromopentane waε added and the εolution warmed to -22 °C and εtirred for 7 h. Extraction and chromatography provided the title compound aε an oil. Example 30. Preparation of N-Trimethylεilylethoxymethyl-5- (3 ' - (2"- toεyloxyethyl) -4' -methylphenyl)tetrazole. A mixture of 1.0 mmol of 3-bromo-4-methylbenzoic acid, 1.2 mmol of DCC, 1.0 mmol of 3-aminopropionitrile in 2 mL of DMF waε εtirred for 36 h at 0°C. Chromatography provided N- (3-cyanopropyl) - (3 ' -bromo-4' -methylphenyl) carboxamide. A εolution of 1.0 mmol of this amide, 4.0 mmol of TMSN3 , 4.0 mmol of PPΪ13 , and 4.0 mmol of DEAD in 4 mL of THF at 0°C was stirred 24 h and then concentrated. The residue was mixed with 5 L of THF and 12.0 mmol of IN NaOH. After stirring for 24 h and processing by extraction, 5- (3 ' -bromo-4' - methylphenyl) tetrazole was obtained. A solution of 1.0 mmol of this tetrazole, 2.0 mmol of SEMC1 in 10 mL DMF was εtirred for 1 h. 2.0 mmol of allyltributyltin and 0.1 mmol of Pd(Ph3>4 waε added and heated at 70 °C for 14 h. Chromatography provided N-trimethylsilylethoxymethyl-5- (3 ' -allyl-4' - methylphenyl) tetrazole. Thiε compound waε ozonized and converted to the title toεylate by methods described previouεly. Example 31. Preparation of 6 ,7-Dihvdroimidazo[ , 5-dl .1■ 31diazepin-8 (3H) - one. A εuεpension of 10 g of 6,7-dihydroimidazo- [4, 5- d] [1, 3]diazepin-8 (3H) -one hydrochloride DMSO solvate (prepared by the method of Chan, et al. , J. Orσ. Chem. 1982, 47, 3457- 3464) in 50 mL triethylamine was stirred for 30 min., 500 mL CH2CI2 waε added, the mixture εtirred for 10 min and filtered. The solid was collected and washed with CH2CI2 to provide the title compound: mp 260 °C. Example 31 . Preparation of 6,7-Dihvdro-5-methylimidazo .4.5- dl .1.31diazepin-8 (3H) -one. The compound 6,7-dihydro-5-methylimidazo[4, 5- d] [1, 3]diazepin-8 (3H) -one hydrochloride (prepared by the method of Showalter, et al. , J. Med. Chem. 1983, 26, 1478) was converted to its freebase, the title compound, by a previously described method. Example 32. Preparation of 6, 7-Dihvdro-7-methylimidazo.4 , 5- dl .1,31diazepin-8 (3H) -one. A mixture of 1 mmol of l-benzyl-5-nitro-lH-imidazole-4- carboxylic acid (prepared by the method of Chan, et al. , J. Orσ. Chem. 1982, 47, 3457-3464) and 1.25 mmol of carbonyldiimidazole in 2 mL of THF was refluxed for 30 min and then cooled to 0 °C and added to a premixed suspension of 4 mmol of nitroethane and 1.5 mmol of potassium t-butoxide in 1.5 mL of THF at 0 °C. After stirring for 6 h at rt, extraction provided 2-nitro-l- (1' -benzyl-5' -nitro-1'H- imidazol-4' -yDpropanone as an oil. A mixture of 1 mmol of this compound and 20 mg of palladium hydroxide on carbon in 5 mL of water adjusted to pH 2 with HCl was subjected to 45 psi H2 for 2 h and then filtration and evaporation provided 2-amino-l- (5' -amino-1'H- imidazol-4' -yDpropanone dihydrochloride as a deliquescent solid . A mixture of 1 mmol of this compound and 4 mmol of triethylorthoformate in 4 mL of ethanol waε refluxed for 2 h and then concentrated and collected by filtration. The solid collected waε freebased by a previouεly deεcribed method to provide the title compound as a deliquescent εolid. Example 33. General Procedure for Alkylation of 6 ,7-Dihvdroimidazof4 , 5- dl ri.3 ldiazepin-8 (3H) -one and Reduction to the 3- Alkylcoformvcin Aσlvcone Derivative. A εuspension of 1.1 mmol sodium hydride and 1 mmol of 6,7-dihydroimidazo [4,5-d] [1,3]diazepin-8 (3H) -one in 10 mL DMF waε εtirred at rt for 0.5 h. Then 1 mmol of the electrophile and 0.25 mmol of Nal were added and the mixture heated at 80 °C for 1 h. Chromatography provided the 3-alkyl-8- ketocoformycin aglycone derivative. To a solution of this derivative (1 mmol) in 3 mL of 1:1 CH2CI2 :methanol waε added 1 mmol NaBH4 and the mixture stirred for 30 min. Chromatography provided the 3-alkylcoformycin aglycone derivative. The following compoundε were prepared in thiε manner: 3- (3 ' -carboethoxypropyl) coformycin aglycone, mp 109-112 °C; 3- (3 ' -carbobenzyloxypropyl) coformycin aglycone, mp 116-117 °C ; 3- (4' -carbomethoxybutyl) coformycin aglycone, mp 136-139 °C; 3- (5 ' -carboethoxypentyl) coformycin aglycone, mp 115-118 °C; 3- (6' -carboethoxyhexyl) coformycin aglycone, mp 117-118 °C; 3- (7 ' -carbomethoxyheptyl)coformycin aglycone, mp 131-133 °C; 3- (5' -carboethoxy-6' -phenylhexyl) coformycin aglycone, mp 121- 124 °C; 3- (5' -carboethoxy-6' - (2"-bromophenyl)hexyl) coformycin aglycone, mp 122-125 °C; 3- (5' -carboethoxy-6' - (3"-bromophenyl)hexyl) coformycin aglycone, mp 125-127 °C; 3- (5' -carboethoxy-6' - (4"-bromophenyl)hexyl) coformycin aglycone, mp 114-116 °C; N- (3- (3' , 6' ,7' ,8'-tetrahydroimidazo[4' , 5' -d] - [1' , 3 ' ]diazepin- 8' -ol-3 ' -yl)propyl) -N-formyl-D-phenylalanine methyl eεter aε a deliqueεcent εolid; N-(3-(3',6',7', 8'-tetrahydroimidazo[4' , 5' -d] - [1' , 3 ' ]diazepin- 8' -ol-3 ' -yl)propyl) -N-formyl-L-phenylalanine methyl eεter aε a deliqueεcent εolid; 3- (5', 5' -dicarboethoxyhexyl)coformycin aglycone, mp 122-125 °C; 3- (5', 5' -dicarbobenzyloxyhexyl) coformycin aglycone, mp 113- 116 °C; 3- (5' , 5' , 5' -tricarbobenzyloxypentyl) coformycin aglycone aε a deliqueεcent εolid; 3- (2 ' - (2"-carboethoxycyclopropyl) ethyl) coformycin aglycone cyclopropane iεomerε, mp 80-88 °C; 3- (4 ' -carbomethoxybenzyl) coformycin aglycone, mp 185-186 °C; 3- (4' -carbomethoxymethylbenzyl) coformycin aglycone, mp 170- 171 °C; 9f 3- (3 ' -carboethoxymethylbenzyl) coformycin aglycone, mp 119 °C; 3- (2'- (2"-carbomethoxyphenoxy)ethyl)coformycin aglycone, mp 180-181°C; 3- (4' -carbomethoxyphenylethyl) coformycin aglycone, mp 188-189 °C; 3- (2 ' - (2"-carbomethoxyphenylthio) ethyl) coformycin aglycone, mp 179-180 °C; 3- (2 ' - (2"-carbomethoxy-6"-isopropylphenylthio) ethyl) - coformycin aglycone, mp 154 °C; 3- (3 '- (2"-carbomethoxyphenyDpropyl)coformycin aglycone, mp 144 °C; 3- (3 '- (2"-carbomethoxynaphthyl)propyl) coformycin aglycone, mp 98-100 °C; 3- (2 '- (3"-carbomethoxynaphthyl) ethyl) coformycin aglycone, mp 238 °C; 3- (cis-2' - (carbomethoxyethyl)cyclohexylmethyl)coformycin aglycone, mp 135-140 °C; 3- (3 '- (3"-carbomethoxyphenyDpropyl) coformycin aglycone, mp 140-145 °C; 3- (3 ' -carbomethoxyphenylmethy1) coformycin aglycone, mp 205-207 °C; 3- (3 ' - (3"-carbomethoxy-6"-methylphenyl)propyl)coformycin aglycone, mp 165-168 °C; 3- (3 ' - (3"-N-methylcarboxamido-6"-methylphenyl)propyl) - coformycin aglycone, mp 205 °C; 3- (3 ' - (2"-carbomethoxy-5"-methylphenyl)propyl) coformycin aglycone, mp 165-170 °C; /O O 3- (3 ' - (2"-carbomethoxy-4"-methylphenyl)propyl) coformycin aglycone, mp 144 °C; 3- (3 ' - (2"-carbomethoxy-3"-fluorophenyl)propyl) coformycin aglycone, mp 131 °C; 3- (2 ' - (3"-carboethoxy-5"-ethylphenyl) ethyl) coformycin aglycone, mp 141 °C; 3- (2' - (3"-bromo-5"-carboethoxyphenyl)ethyl) coformycin aglycone, mp 132 °C; 3- (2 ' - (3"-carboethoxybiphen-5"-yl)ethyl) coformycin aglycone, mp 160 °C; 3- (2 ' - (3"-carbomethoxy-6"-methylphenyl) ethyl) coformycin aglycone, mp 199-201 °C; 3- (2 ' - (3"-carboethoxy-6"-methylphenyl) ethyl) coformycin aglycone, mp 145-150 °C; 3- (2 ' - (3"-carbobenzyloxy-6"-methylphenyl) ethyl) coformycin aglycone, mp 80-85 °C; 3- (2 ' - (3"-carboethoxy-6"-t-butyldimethylsilyloxy- methylphenyl) ethyl) coformycin aglycone aε a deliqueεcent solid and standard treatment of this compound with TBAF provided 3- (2' - (3"-carboethoxy-6"-hydroxymethylphenyl) ethyl) coformycin aglycone as a deliqueεcent εolid; 3- (2' - (3"-carbomethoxy-6"-ethylphenyl)ethyl) coformycin aglycone, mp 159 °C; 3- (2 ' - (3"-carbomethoxy-6"-propylphenyl) ethyl) coformycin aglycone, mp 164 °C; 3- (2 ' - (3"-carboethoxy-4"-methylphenyl) ethyl) coformycin aglycone, mp 155-156 °C; fθ/ 3- (2 '- (3"-carbomethoxyphenyD ethyl) coformycin aglycone, mp 143 °C; 3- (3 ' - (2"-methoxy-5"-carbomethoxyphenyDpropyl)coformycin aglycone, mp 164 °C; 3- (2 ' - (2"-methoxy-5"-carbomethoxyphenyDethyl) coformycin aglycone, mp 190-195 °C; 3- (2 ' - (2"-fluoro-5"-carbomethoxyphenyDethyl) coformycin aglycone, mp 203-205 °C; 3- (2' - (3"-carbomethoxy-4"-fluorophenyl)ethyl)coformycin aglycone, mp 179-180 °C; 3- (2 '- (3"-carbomethoxyphenoxy) ethyl) coformycin aglycone, mp 168-170 °C; 3- (3 ' - (2"-carbomethoxyfuran-5"-yl)propyl) coformycin aglycone, mp 120-122 °C; 3- (2' -carboethoxyfuran-5' -ylmethyl) coformycin aglycone, mp 130-135 °C; 3- (2 ' - (2"-carbomethoxythiophen-4"-yl) ethyl) coformycin aglycone, mp 171 °C; 3- (3 ' - (2"-carbomethoxythiophen-3"-yl)propyl) coformycin aglycone, mp 187 °C; 3- (3 '- (2"-carbomethoxy-3"-methyl-6"- iεopropylphenyl)propyl) coformycin aglycone, mp 175-180 °C; 3- (3'- (2"-carbomethoxy-6"-isopropylphenyl)propyl) coformycin aglycone, mp 168-170 °C; 3- (5' - (dimethyl phosphonyDpentyl) coformycin aglycone, mp 80- 81 °C; 3- (6'- (dimethyl phoεphonyl)hexyl) coformycin aglycone, mp 93- 94 °C ; 3- (5'- (dibenzyl phosphonyl)pen yl) coformycin aglycone, mp 81- 82 °C; 3- (6 '- (dibenzyl phosphonyl) exyl) coformycin aglycone, mp 71- 72 °C; 3- (2 ' -acetoxyethyl) coformycin aglycone, mp 164-165 °C; 3- (3 ' -acetoxypropyl) coformycin aglycone, mp 103-104 °C; 3- (4 ' -acetoxybutyl) coformycin aglycone, mp 134-135 °C; 3- (5 ' -acetoxypentyl) coformycin aglycone, mp 93-94 °C; 3- (6 ' -acetoxyhexyl) coformycin aglycone, mp 107-108 °C; 3- (4 ' -cyanobutyl) coformycin aglycone, mp 146-149 °C; 3- (6 ' -cyanohexyl) coformycin aglycone, mp 129-132 °C; 3-ethylcoformycin aglycone, mp 189-190 °C; 3-propylcoformycin aglycone, mp 159-160 °C; 3-butylcoformycin aglycone, mp 163-164 °C; 3- (3 ' -butenyl) coformycin aglycone, mp 151-152 °C; 3-hexylcoformycin aglycone, mp 159-160 °C; 3-heptylcoformycin aglycone, mp 152-153 °C; 3-octylcoformycin aglycone, mp 151-152 °C; 3-nonylcoformycin aglycone, mp 149-150 °C; 3- (trans-3 ' , 7 ' -dimethyl-2' , 6' -octadienyl)coformycin aglycone, mp 156-158 °C; (3 'R) -3- (3 ' , 7 ' -dimethyloct-6' -enyl) coformycin aglycone, mp 167-168 °C; (3 'S) -3- (3 ' , 7 ' -dimethyloct-6' -enyl) coformycin aglycone, mp 164-165 °C; (3 'S) -3- (3 ' , 7' -dimethyloctyl)coformycin aglycone, mp 170-171 °C ; 3- (4 ' -methyl-3 ' -pentenyl)coformycin aglycone, mp 160-161 °C; 3-cyclohexylmethylcoformycin aglycone, mp 198-199 °C; 3-cycloheptylmethylcoformycin aglycone, mp 199-200 °C; (l'S,2'S,5'S)-3-(6' , 6' -dimethyl[3,1,1] -bicyclohept-2 '- methyl) coformycin aglycone, mp 207-208 °C; (l"R,2"S,5"R)-3- (2'- (2"-isopropyl-5"-methylcyclohexyloxy) - ethyl) coformycin aglycone, mp 168-169 °C; (1"S, 2"R, 5"S) -3- (2 ' - (2"-isopropyl-5"-methylcyclohexyloxy) - ethyl) coformycin aglycone, mp 168-169 °C; 3- (2 ' -cyclohexylethyl)coformycin aglycone, mp 205-206 °C; 3- (3 ' -cyclohexylpropyl) coformycin aglycone, mp 180-181 °C; 3- (2 ' -cyclopentylethyl) coformycin aglycone, mp 205-206 °C; 3- (naphth-2' -ylmethyl) coformycin aglycone, mp 190-191; 3- (2 '-(naphth-2"-yl) ethyl) coformycin aglycone, mp 192-193 °C; 3- (2 ' -phenylethyl)coformycin aglycone, mp 146-147 °C; 3- (2 '- (2"-methylphenyl) ethyl) coformycin aglycone, mp 180-185 °C; 3- (3 ' -phenylpropyl) coformycin aglycone, mp 157-158 °C; 3- (3 ' - (2" ,3" , 4" , 5"-tetrafluorophenyl)propyl) coformycin aglycone, mp 188-189 °C; 3- (3 ' -phenyl-2 ' -propenyl) coformycin aglycone, mp 168-169 °C; 3- (3 '- (2"-methylphenyl)propyl) coformycin aglycone, mp 193-195 °C; 3- (3 ' - (2"-trifluoromethylphenyl)propyl) coformycin aglycone, mp 188-192 °C; 3- (3 '- (3"-methylthiophen-2"-yl)propyl) coformycin aglycone, mp 185 -190 °C ; 3- (3 '- (2"-chlorophenyDpropyl) coformycin aglycone, mp 181-182 °C; 3- (3 '- (3"-chlorophenyDpropyl) coformycin aglycone, mp 171-172 °C; 3- (3 '- (4"-chlorophenyDpropyl) coformycin aglycone, mp 157-158 °C; 3- (3 '- (2"-bromophenyl)propyl) coformycin aglycone, mp 186-187 °C; 3- (3 '- (3"-bromophenyl)propyl) coformycin aglycone, mp 165-166 °C; 3- (3 '- (4"-bromophenyl)propyl) coformycin aglycone, mp 147-148 °C; 3- (3 '- (2"-ethoxyphenyl)propyl) coformycin aglycone, mp 168-169 °C; 3- (3 '- (3"-ethoxyphenyl)propyl)coformycin aglycone, mp 136-137 °C; 3- (3 '- (4"-ethoxyphenyl)propyl) coformycin aglycone, mp 117-11. °C; 3- (3 '- (2"-benzyloxyphenyl)propyl)coformycin aglycone, mp 129- 130 °C; 3- (3 '- (3"-benzyloxyphenyl)propyl)coformycin aglycone, mp 123- 124 °C; 3- (3 '- (4"-benzyloxyphenyl)propyl)coformycin aglycone, mp 154- 155 °C; 3- (3 '- (4"-methoxyphenyl)propyl) coformycin aglycone, mp 165- 166 °C; 3- (3 ' - (4"-trifluoromethoxyphenyDpropyl) coformycin aglycone, mp 123-124 °C; 3- (3 '- (4"-propoxyphenyl)propyl) coformycin aglycone, mp 134-135 °C; 3- (3 '- (4"-butoxyphenyl)propyl) coformycin aglycone, mp 135-136 °C; 3- (3 '- (4"-iεopropylphenyl)propyl) coformycin aglycone, mp 161- 162 °C; 3- (3 '- (4"-propylphenyl)propyl) coformycin aglycone, mp 139-140 °C ; 3- (3 '- (biphenyl-4"-yl)propyl) coformycin aglycone, mp 174-175 °C; 3- (3 ' - (2" , 4"-dimethylphenyl)propyl)coformycin aglycone, mp 167 °C; 3- (3 '- (2" , 5"-dimethylphenyl)propyl) coformycin aglycone, mp 174 °C; 3- (3 ' - (2" , 4" , 6"-trimethylphenyl)propyl)coformycin aglycone, mp 181 °C; 3- (2 ' -phenylbutyl) coformycin aglycone, mp 161-162 °C; and 3- (6' - (2"-bromophenyl)hexyl) coformycin aglycone, mp 136-137 °C. Example 34. Preparation of 3- (3 '- (Hvdroxyphenyl)propyl) coformycin Aσlvconeε. The 3- (3 '- (benzyloxyphenyl)propyl) coformycin aglycone waε hydrogenated using previously described conditions to provide the title compound. The following compounds were prepared in this manner: 3- (3 '- (2"-hydroxyphenyl)propyl) coformycin aglycone, mp 140-141 °C; 3- (3 '- (3"-hydroxyphenyl)propyl) coformycin aglycone, mp 144-145 °C; and 3- (3 '- (4"-hydroxyphenyl)propyl) coformycin aglycone, mp 123-124 °C. Example 35. Preparation of 5-Methyl-3- (3 ' - (2"-methylphenyl)propyl) - coformycin aσlvcone. The compound 6, 7-dihydro-5-methylimidazo[4, 5- d] [1, 3 ]diazepin-8 (3H) -one was alkylated and reduced by a previously deεcribed method to provide the title compound: mp 82 °C. Example 36. Preparation of 3- (3 ' - (2"-Methylphenv proPyl) -4.5.6 , 8- tetrahvdro-7H-imidazo .4.5-dl [1 , 31diazepine-5-one-8-ol. The compound 4, 5, 6, 8-tetrahydro-lH,7H-imidazo[4, 5- d] [l,3]diazepine-5, 8-dione (prepared by the method of Hoεmane, et al., Nucleoεides & Nucleotideε 1991, 10, 1693-1706) waε alkylated and reduced by a previouεly deεcribed method to provide the title compound: mp 218 °C. Example 37. Preparation of 7-Methyl-3- (3 ' -phenylpropyl) coformycin aσlvconeε. The compound 6,7-dihydro-7-methylimidazo[4, 5- d] [1, 3]diazepin-8 (3H) -one was alkylated and reduced by a previously described method to provide a mixture of the title compounds: mp 89-90 °C. Example 38. Preparation of 3-Cvcloheptylcoformvcin Aσlvcone. A mixture of 1 mmol 6,7-Dihydroimidazo[4, 5- d] [1, 3]diazepin-8 (3H) -one (1.3 mmol), 1 mmol cycloheptylbromide and 2 mmol CS2CO3 in 5 mL of DMF was stirred for 4 h at 75 °C. Chromatography provided 3- cycloheptyl-8-ketocoformycin aglycone which wε reduced with εodium borohydride aε previously described to produce the title compound: mp 187-189 °C . Example 39. Preparation of 3-Substituted 6-Acetylcoformvcin A lvcones. A mixture of 1 mmol of a 3-substituted coformycin aglycone and 3 mmol of thioacetic acid in 10 mL of DMF waε εtirred at rt for 16 h. Chromatography provided the title compound. The following compoundε were prepared in this manner: 3-heptyl-6-acetylcoformycin aglycone, mp 138-141 °C; and 3- (3 ' -phenylpropyl) -6-acetylcoformycin aglycone as a deliquescent solid. Example 40 . Preparation of 3-εubεtituted-8-heterosubstituted-3 , 6 ,7.8- tetrahvdroimidazo [4 , 5-d1 [1,31 diazepine. A mixture of 1 mmol of the 3-εubstituted 6- acetylcoformycin aglycone, 3 mmol of DEAD, 3 mmol of PPh3 and 3 mmol of thioacetic acid or diphenylphosphorylazide in 10 mL of THF waε εtirred at 0 °C for 6 h. Chromatography provided the 8-εubεtituted compound which after stirring in methanolic ammonia for 30 min at 0 °C and evaporating the solvent provided the title compounds. The following compounds were prepared in this manner: 3-heptyl-8-mercapto-3 ,6,7, 8-tetrahydroimidazo[4, 5- d] [1,3]diazepine as an oil, 3- (3 ' -propylphenyl) -8-azido-3 ,6,7, 8-tetrahydroimidazo[4,5- d] [1,3]diazepine as an oil and 3- (3 ' -propylphenyl) -8-amino-3,6,7, 8-tetrahydroimidazo[4, 5- d] [1, 3]diazepine as an oil from hydrogenation of the 8-azido analog under previously described conditionε. Example 41. Preparation of 3-Heptyl-8-methylcoformvcin Aσlvcone. A mixture of 1 mmol of 3-heptyl-8-ketocoformycin aglycone and 1.1 mmol of NaH in 5 mL of DMF waε stirred for 30 min and then 1.1 mmol of trimethylsilylethoxymethyl chloride (SEM-Cl) was added and after εtirring for 6 h, extraction and chromatography provided the 6-SEM εubεtituted derivative. To a εolution of 1 mmol of thiε compound in 10 mL of THF at -78 °C waε added 3 mmol of etheral MeLi and after 1 h, extraction and chromatography provided 3-heptyl-6-SEMyl-8- methylcoformycin aglycone. A mixture of 1 mmol of thiε compound and 1.5 mmol of TBAF in 10 mL of DMF was stirred at 80 °C for 3 h and then chromatography provided the title compound: mp 133-136 °C. Example 42. General Procedure for Ester Hvdrolvsiε to a Sodium Carboxylate. The eεter (1mm) was stirred at rt in 13 mL of 0.1 N sodium hydroxide for 2 h and then the pH lowered to 7 by the addition of Amberlite CG-50 resin. The εolution waε filtered over Celite and lyophilized to provide the carboxylate εodium εalt. The following compounds were prepared in this manner: 3- (5 ' -carboxypentyl) coformycin aglycone εodium salt, mp 250 °C (dec) ; 3- (6 ' -carboxyhexyl) coformycin aglycone, mp 165-168 °C; 3- (7' -carboxyheptyl)coformycin aglycone, mp 166-166; 3- (3 ' -carboxypropoxymethyl)coformycin aglycone sodium salt as a deliquescent solid; 3- (5' -carbobenzyloxy-5' -carboxyhexyl) coformycin aglycone sodium salt, and in thiε caεe, dioxane in a volume equivalent to that of sodium hydroxide was added to provide the title compound, mp 62-65 °C; I /O 3- (2'- (2"-carboxycyclopropyl) ethyl) coformycin aglycone sodium salt as a deliquescent solid, 3- (2 '- (o-carboxyphenoxy) ethyl) coformycin aglycone sodium salt as a deliquescent solid, 3- (p-carboxyphenylethyl) coformycin aglycone sodium salt as a deliquescent solid, 3- (p-carboxymethylbenzyl) coformycin aglycone sodium salt as a deliquescent solid, 3- (2 '- (o-carboxyphenylthio) ethyl) coformycin aglycone sodium salt as a deliquescent solid, 3- (2 '- (m-carboxyphenoxy) ethyl) coformycin aglycone sodium salt as a deliquescent solid, 3- (3 ' - (3"-carboxy-6"-methylphenyl)propyl) coformycin aglycone sodium εalt aε a deliquescent solid, 3- (3 '- (o-carboxyphenyl)propyl) coformycin aglycone sodium salt as a deliquescent solid, 3- (3 '- (m-carboxyphenyl)propyl) coformycin aglycone sodium εalt aε a deliquescent solid and 3- (3 '- (mercaptoacetoxy)propyl) coformycin aglycone sodium salt as a deliquescent εolid. Example 43. General Procedure for Eεter Hvdrolvεis to a Carboxylic Acid. One mmol of the eεter waε εtirred at rt in 13 mL of 0.1 N sodium hydroxide for 2 h and then the solution was εubjected to ion exchange chromatography on Dowex-1-acetate eluting firεt with water and then with 0.1 N acetic acid to provide the deεired carboxylic acid. The following compounds were prepared in this manner: 3- (5' -carboxy-6' -phenylhexyl) coformycin aglycone, prepared as described only an equal volume of dioxane was added and the mixture was heated for 16 h at 60 °C to effect hydrolysiε, mp 58-61 °C; 3- (5' -carboxy-6' - (2"-bromophenyl)hexyl) coformycin aglycone, mp 111 °C; 3- (5' -carboxy-6' - (3"-bromophenyl)hexyl)coformycin aglycone, mp 98 °C; 3- (5' -carboxy-6' - (4"-bromophenyl)hexyl)coformycin aglycone, mp 116 °C; N- (3- (3' ,6' ,7' ,8'-tetrahydroimidazo[4' , 5' -d] - [1' , 3 ' Jdiazepin- 8 '-ol-3'-yl)propyl) -N-formyl-D-phenylalanine, 118-122 °C; N- (3- (3' , 6' ,7' ,8' -tetrahydroimidazo[4' , 5' -d] - [1' , 3 ' Jdiazepin- 8' -ol-3 '-yl)propyl) -N-formyl-L-phenylalanine, 118-122 °C; 3- (5', 5' -dicarboxypentyl)coformycin aglycone, prepared as described from 3- (5', 5', 5' -tricarbobenzyloxypentyl)coformycin aglycone only an equal volume of dioxane and 2 mmol of NaOH were added and the product was isolated by ion exchange chromatography and preparative reverse phase chromatography, mp 85-90 °C; 3- (5' -carboxy-5' -carbobenzyloxypentyl) coformycin aglycone, prepared as described from 3-(5',5',5'- tricarbobenzyloxypentyl) coformycin aglycone only an equal volume of dioxane and 2 mmol of NaOH were added and the product was isolated by ion exchange chromatography and preparative reverse phase chromatography, mp 53-58 °C. 3- (3 ' - (2"-carboxy-5"-methylphenyl) ropyl) coformycin aglycone, mp 122-125 °C; 3- (3 ' -carboxyphenylmethyl) coformycin aglycone, mp 205-207 °C; 3- (3 '- (2"-carboxyfuran-5"-yl)propyl) coformycin aglycone, 190 °C (dec) ; 3- (2 ' -carboxyfuran-5 ' -ylmethyl) coformycin aglycone, mp 240 °C (dec) ; 3- (3 ' - (2"-carboxy-6"-isopropylphenyl)propyl) coformycin aglycone, mp 210 °C (dec); 3- (3 ' - (2"-methoxy-5"-carboxyphenyDpropyl) coformycin aglycone, mp 225 °C; 3- (3 ' - (2"-fluoro-5"-carboxyphenyDethyl) coformycin aglycone, mp 230-240 °C; 3- (2' - (2"-methoxy-5"-carboxyphenyDethyl) coformycin aglycone, mp 180-190 °C (dec) ; 3- (2 '- (3"-carboxy- "-methylphenyl)ethyl) coformycin aglycone aε a deliqueεcent εolid; 3- (2 ' - (3"-carboxy-4"-fluorophenyl) ethyl) coformycin aglycone, mp 220-230 °C (dec) ; 3- (2 ' - (3"-carboxy-5"-ethylphenyl) ethyl)coformycin aglycone, mp 130 °C (dec) ; 3- (2 '- (3"-carboxybiphen-5"-yl) ethyl) coformycin aglycone, mp 220 °C (dec) ; 3- (2 '- (3"-bromo-5"-carboxyphenyDethyl) coformycin aglycone, mp 226 °C; 3- (2 ' - (3"-carboxy-6"-methylphenyl) ethyl) coformycin aglycone, mp 140 - 150 °C ; 3- (2 ' - (3"-carboxy-6"-ethylphenyl)ethyl)coformycin aglycone, mp 215 °C; 3- (2 ' - (3"-carboxy-6"-propylphenyl) ethyl) coformycin aglycone, mp 250 °C; 3- (2 ' - (3"-carboxy-6"-hydroxymethylphenyl) ethyl) coformycin aglycone, mp 140-150 °C; 3- (2 '- (3"-carboxyphenyD ethyl)coformycin aglycone, mp 210 °C; 3- (3 ' - (2"-carboxy-3"-fluorophenyl)propyl) coformycin aglycone, mp 205 °C; 3- (3 ' - (2"-carboxy-4"-methylphenyl)propyl) coformycin aglycone, mp 204 °C; 3- (3 ' -carboxymethylbenzyl) coformycin aglycone, mp 207 °C; 3- (3 '- (2"-carboxynaphthyl)propyl) coformycin aglycone, mp 200- 210 °C; 3- (2 '- (3"-carboxynaphthyl)ethyl)coformycin aglycone, mp 190- 235 °C (dec) ; 3- (3 ' - (2"-carboxythiophen-3"-yl)propyl) coformycin aglycone, mp 210 °C (dec) ; 3- (2'- (2"-carboxythiophen-4"-yl)ethyl)coformycin aglycone, mp 230 °C (dec) ; 3- (2'- (2"-carboxythiophen-5"-yl)ethyl) coformycin aglycone as a deliquescent solid and 3-carboxyethylthioethylcoformycin aglycone, mp 106 °C. Example 44. Preparation of N- (4- (3 ' , 6' , 7 ' , 8' -Tetrahvdroimidazo- r4' , 5' -dl - r1' .3 ' 1diazepin-8' -ol-3 ' -yl)butyryl)σlvcine Dicvclohexyl Ammonium Salt. General Procedure for the Svntheεiε of Amino Acid Adductε. A mixture of 1 mmol of 3- (3 ' -carbobenzyloxypropyl) - coformycin aglycone and 10 mg of 10 % Pd/C in 4 mL of methanol was subjected to hydrogenation. After filtration and removal of the solvent, 3- (3 ' -carboxypropyl) coformycin aglycone waε obtained. This product, 2 mmol glycine ethyl ester hydrochloride, 2 mmol triethylamine, 2 mmol dicyclohexylcarbodiimide and 2 mmol N-hydroxysuccinimide in 10 mL DMF were εtirred 16 h and filtered. Chromatography provided N- (4- (3 , 6, 7, 8-tetrahydro-imidazo[4, 5-d] - [1, 3]diazepin-8-ol-3-yl)butyryl)glycine ethyl ester. Thiε eεter was hydrolyzed as previously described to provide N- (4- (3 , 6, 7, 8-tetrahydroimidazo[4,5-d]-[l,3]diazepin- 8-ol-3-yDbutyryl)glycine. To a solution of this acid in methanol was added dicyclohexylamine and then the solvent evaporated and the residue triturated with acetone to provide the title compound: mp 222 °C. The following compounds were prepared in this manner: N- (4- (3' ,6' ,7' ,8' -tetrahydroimidazo[4' , 5' -d] - [1' , 3 ' ]diazepin- 8' -ol-3 ' -yl)butyryl) -L-phenylalanine dicyclohexyl ammonium Salt, mp 220 °C; N-(4-(3',6',7',8' -tetrahydroimidazo- [4' ,5'-d]-[l',3' ]diazepin- 8' -ol-3 ' -yDbutyryl) -D-phenylalanine dicyclohexyl ammonium salt, mp 162-165 °C; and N-(4-(3',6',7' ,8' -tetrahydroimidazo- [4' ,5'-d]-[l',3' ]diazepin- l/ 8' -ol-3 ' -yl)butyryl) -L-valine Dicyclohexyl Ammonium Salt, mp 223 °C. Example 45. Preparation of 3- ( ' -Carbox-N-εubεtituted-amido-5 ' - carboxyhexyl) coformvcin Aσlvcones. A mixture of 1 mmol of 3- (5' -carbobenzyloxy-5' - carboxyhexyl) coformycin aglycone, 1.5 mmol of an amine, 1.5 mmol of diphenylphosphorylazide and 3 mmol of triethylamine in 10 mL of DMF were stirred at 16 h at rt. Chromatography provided the ester-amide compound which was subjected to ester hydrolysis by the previously described method to provide the title compound. The following compoundε were prepared in thiε manner: 3- (5' -carbox-N-benzylamido-5' -carboxyhexyl) coformycin aglycone, mp 175 °C; 3- (5' -carbox-N- (4"-chlorobenzyl)amido-5' - carboxyhexyl) coformycin aglycone, mp 111 °C; 3- (5' -carbox-N- (2"-phenethyl)amido-5' -carboxyhexyl) coformycin aglycone, p 93 °C; 3- (5' -carbox-N-cyclohexylamido-5' -carboxyhexyl)coformycin aglycone, mp 199-203 °C; and 3- (5' -carbox-N-cyclohexylmethylamido-5' - carboxyhexyl) coformycin aglycone, mp 116 °C. Example 46. Preparation of 3- (5' -Carboxamido-5 ' -carboxyhexyl) coformycin 1/6 Aαlvcone. The compound 3- (5' -carbox-N-phenylamido-5' - carbobenzyloxyhexyl) coformycin aglycone, prepared as above was subjected to hydrogenation by the previously described method to provide the title compound: mp 170 °C. Example 47. Preparation of 3- (5'- (Tetrazol-5"-vl) entvl) coformycin aσlvcone dicvclohexylamrrtonium salt. 6,7-Dihydroimidazo[4, 5-d] [1,3]diazepin-8 (3H) -one and 5- (5' -bromopentyl) -2-trimethylsilylethoxymethyltetrazole were subjected to the general alkylation and reduction sequence to provide 3- (5 ' - ( (2"-trimethylsilylethoxy-methyl) tetrazol-5"- yDpentyl) coformycin aglycone as a deliquescent solid. A mixture of 1 mmol of this compound and 1.5 mmol of TBAF in 10 mL of DMF were stirred at 50 °C for 2 h. The mixture waε evaporated and the reεidue diεεolved in 5 mL of water and εubjected to ion-exchange chromatography on Dowex-1-acetate eluting with water and then 0.05 M AcOH to give the tetrazole. it waε dissolved in methanol and dicyclohexylamine was added. Evaporation and trituration with acetone provided the title compound: mp 220 °C. The following compound was also prepared in thiε manner: 3- (2 ' - (6"-methyl-3"- (tetrazol-5' "-yl)phenyl)ethyl) coformycin aglycone: mp 190 °C (dec) . Example 48. t/4 Preparation of 3- (6'- (Methyl phosphonoxy)hexyl) coformycin Aσlvcone. A solution of 1 mmol of 3- [6'- (dimethyl phosphonyl)hexyl]coformycin aglycone and 20 mmol lithium methoxide in 10 mL of methanol was stirred for 72 h at 50 °C. The mixture was cooled and methanolic HCl was added to pH to 1. Reverse phase chromatography provided the title compound: mp 67-68 °C. Example 49. Preparation of 3- (5' -Phosphonoxypentyl)coformycin Aσlvcone. A suspension of 1 mmol of 3- [5' - (dibenzyl phosphonyl)pentyl]coformycin aglycone and 50 mg of 10 % Pd/C in 10 mL of 1:1 water-methanol was hydrogenated. The mixture was filtered through Celite, concentrated and lyophilized to provide the title compound: mp 119-120 °C. The following compounds were prepared in this manner: 3- (6' -phosphonoxyhexyl)coformycin aglycone, mp 210 °C (dec); and 3- (5', 5' -dicarboxyhexyl)coformycin aglycone dicyclohexyl ammonium salt, prepared in the same manner only dicyclohexylammine was included during hydrogenation, mp 155 °C (dec) . Example 50. General Procedure for Acetate Methanolysis to a 3- (Hvdroxyalkyl) coformycin Aσlvcone. A εolution of 1 mmol of 3- (acetoxyalkyl) coformycin aglycone and 5 mL of a 0.5 M εolution of εodium methoxide in methanol was stirred for 0.5 hours. Amberlite CG-50 resin was added until pH 7. Filtration throough celite, solvent removal and crystallization from ether-methanol provided the title compound. The following compounds were prepared in this manner: 3- (2 ' -hydroxyethyl) coformycin aglycone, mp 220-221 °C; 3- (3 ' -hydroxypropyl) coformycin aglycone, mp 210-211 °C; 3- (4 ' -hydroxybutyl) coformycin aglycone, mp 176-177 °C; 3- (5 ' -hydroxypentyl) coformycin aglycone, mp 135-136 °C; and 3- (6 ' -hydroxyhexyl) coformycin aglycone, mp 138-139 °C. Example 51. Preparation of 3- (5 ' -Carboxamidopentyl) coformycin Aσlvcone. A solution of 3- (5' -carboethoxypentyl)coformycin aglycone in 4 mL of a 15 % NH3 in methanol solution was heated in a εealed reaction vessel at 100 °C for 72 h. Then the solvent was removed and the reεidue recryεtallized from ether-methanol to provide the title compound: mp 159-163 °C (dec) . For the purposes of clarity and brevity, chemical compounds are referred to as numbers in the biological exampleε below. The following is a list of the chemical names associated with the compound numbers: 3-heptylcoformycin aglycone (compound la) , 3-heptyl-8-methylcoformycin aglycone (compound lb) , (3'S)-3-(3',7' -dimethyloct-6' -enyl) coformycin aglycone (compound lc) , //f 3-cycloheptylcoformycin aglycone (compound Id) , (l'S,2'S,5'S)-3-(6',6' -dimethyl [3,1,1] -bicyclohept-2' - methyl) coformycin aglycone (compound le) , 3- (3 '- (2"-methylphenyl)propyl) coformycin aglycone (compound If), 5-methyl-3- (3 ' - (2"-methylphenyl)propyl) coformycin aglycone (compound lg) , 3- (3 ' -propylphenyl) -8-azido-3,6,7, 8-tetrahydroimidazo[4,5- d] [1, 3]diazepine (compound lh) , 3- (3 '- (4"-propoxyphenyl)propyl)coformycin aglycone (compound ID, 3- (5' -carboxy-6' -phenylhexyl)coformycin aglycone (compound lj ) , 3- (5' -carboxy-5' -carbobenzyloxypentyl) coformycin aglycone (compound Ik) , 3- (5' -carbox-N-benzylamido-5' -carboxyhexyl) coformycin aglycone (compound 11) , 3- (2' - (3"-carboxy-6"-methylphenyl) ethyl) coformycin aglycone (compound lm) , 3- (2' - (6"-methyl-3"- (tetrazol-5' "-yDphenyl)ethyl)coformycin aglycone (compound In) , 3- (2' - (2"-carboxythiophen-4"-yl)ethyl)coformycin aglycone (compound lo) , 3- (2 '- (3"-carboxynaphthyl) ethyl) coformycin aglycone (compound lp ) , 3- (2' - (3"-bromo-5"-carboxyphenyD ethyl) coformycin aglycone (compound lq) and /2-X? 3- (5' -carboxy-6 ' - (3"-bromophenyl)hexyl) coformycin aglycone (compound lr) . Example A AMP Deaminase Asεav Inhibition of AMPDA activity from porcine heart was determined at 37° C in a 0.1 ml assay mixture containing inhibitor, - 0.005 U AMPDA, 0.1% bovine serum albumin, 10 mM ATP, 250 mM KCl, and 50 mM MOPS at pH 6.5. The concentration of the substrate AMP was varied from 0.125 - 10.0 mM. Catalyεis was initiated by the addition of enzyme to the otherwise complete reaction mixture, and terminated after 5 minutes by injection into an HPLC system. Activities were determined from the amount of IMP formed during 5 minutes. IMP was separated from AMP by HPLC using a Beckman Ultrasil-SAX anion exchange column (4.6 mm x 25 cm) with an isocratic buffer εyεtem (12.5 mM potaεεium phoεphate, 30 mM KCl, pH 3.5) and detected spectrophotometrically by absorbance at 254 nm. Valueε of the inhibition conεtant Ki were calculated from the dependence of activity on substrate and inhibitor concentrations aεsuming competitive inhibition: v = Vmax [AMP] / {[AMP] + Km (1 + [I] / Ki) } where v is the measured catalytic rate, Vmax is the maximal rate at saturating concentrations of AMP and in the abεence of inhibitor I, and Km iε the Michaeliε constant for AMP. For ease of comparison, data obtained by thiε aεsay is preεented in the table of example B. Example B Adenosine Deaminase Assay Inhibition of adenosine deaminase (ADA) from calf intestinal mucosa was determined spectrophotometrically at pH 7.0 using one of the following two assayε : (1) Direct aεεay: The reaction εystem mixture contained inhibitor, - 0.001 units ADA, and 40 mM potassium phosphate in 1 ml and at 37° C. The concentration of the substrate adenosine was varied from 20 to 100 μM. The reaction was initiated by addition of ADA and monitored continuously at 265 nm for 15 minutes as the decrease in absorbance reflects conversion of adenosine to inosine. (2) Coupled aεεay based upon the following reaction scheme: ADA GDH Adenosine — ■ ► NHn3; glutamate + NAD + Inosine αKG+NADH+H The reaction mixture contained 100 μM adenosine, - 0.001 U ADA, 2.5 mM a-ketoglutarate (aKG) , 250 μM NADH, 400 μM ADP, ~ 10 U glutamate dehydrogenase (GDH) , and 50 mM potassium phosphate in 0.2 ml and at room temperature. The reaction was initiated by addition of adenoεine and monitored continuously at 340 nm for 7 minutes as the decrease in absorbance reflects oxidation of NADH. The following table gives the inhibition constants for AMPDA and ADA of representative compounds of the present invention. The selectivity ratio was determined aε: selectivity ratio = [ADA Ki/Km] / [AMPDA Ki/Km] . Selectivity Ratio** 0.60 6 29 17 >1.6K 0.34 >150 0.16 0.03 >8.3K >47K >6.3K >175K >2.1K 590 >850K values are in μM ** K = 1,000 Example C Inhibition of Neutrophil-Mvocvte Adhesion Iεolated neutrophils and myocytes were εtimαlated with the cytokine, TNF-α, and incubated in the preεence of the test ιιx3 compound. Neutrophil-myocyte adhesion was determined aε deεcribed by Entman, et al. , J. Clin. Invest. 85:1497-1506 (1990) . The following table gives IC50 values obtained for representative compounds of the preεent invention. Thiε inhibition waε completely reversed in the presence of adenosine deaminase (ADA) , demonstrating inhibition was mediated by increased adenosine levels. Neutrophil-Mvocvte Adhesion Inhibition Compound IC50 (μM) la 12 ± 6 lc 5.1 ± 2.5 Id 4.3 ± 1.3 le 24 ± 3 If 1.4 ± 0.45 Ij 0.045 ± 0.01 lm 0.030 ± 0.01 lo 8.0 ± 2 Example D Improved Functional Recovery in Iεchemic Heartε The ability of AMP deaminaεe inhibitorε of the preεent invention to improve the recovery of poεt-iεchemic function waε examined in an iεolated rat heart model of iεchemia- reperfuεion injury. Iεolated rat heartε were cannulated via the aεcending aorta and attached to a perfuεion apparatus according to the /A method of Langendorff. The hearts were perfused at a constant pressure of 100 cm of H2O with a modified Krebs-Hanseleit buffer (pH 7.4) at 37 °C. Left ventricular developed pressures (LVDP) were monitored continuously using a latex balloon attached to a pressure transducer. Coronary flows were measured gravimetrically by timed collection of pulmonary effluent. Following equilibration of the hearts for a period of 30 minutes, the heartε were subjected to 430 minutes of low flow ischemia, by reducing the perfusion presεure to 10 cm of H2O, and then reperfuεed for 30 minuteε by restoring the pressure to its original level (100 cm of H2O) . Two compounds of the present invention, compound la and compound lm, were tested in this asεay. Compound la provided recovery of LVDP to 83±3% compared to the placebo value of 69±1% when added to the perfuεion to give a concentration of 3 μM. Compound lm provided recovery of LVDP to 83±2% compared to the placebo value of 65±2% when added to the perfuεion to give a concentration of 0.3 μM. Example E Inhibition of Seizures The following compounds of the present invention were examined for ability to inhibit electrically-induced seizures in rats: compound Id, compound le, compound If and compound lc. Maximal electroshock (MES) seizures were induced in male 9- f Sprague Dawley rats by administering a 150 mA, 60-Hz εinewave current for 0.2 sec via corneal electrodes. The MES stimuluε waε preεented 30 min following intraperitoneal injection of the teεt compound. The endpoint meaεured waε percentage of animals in which hind limb tonic extension (HTE) was suppressed; suppression level is 0% in vehicle-treated animals. All of the test compounds elicited 25-67% (n=6 per compound) suppression at a dose of 10-30 mg/kg. These results indicate that AMPDA inhibitors inhibit MES seizures in rats. Example F Effect of AMPDA Inhibitor In A Rat Model Of Ischemic Brain Injury Each rat is anesthetized with halothane and placed on a heating pad hooked up to a temperature regulator and connected to rectal probe. EEG electrodeε are then inεerted into the temporalis muscle bilaterally in between the eye and the ear. A midline incision iε made to expoεe the left Common Carotid Artery (CCA) . The Internal Carotid Artery (ICA) is isolated and carefully separated from the adjacent vagus nerve. Following ligation of various veεεels the ICA should be the only remaining extracranial branch of the CCA. Two 5-0 silk sutures are tied loosely around the external carotid artery (ECA) and micrόvascular clips placed on both the CCA (proximal to the bifurcation) and the ICA (in between the first and the second bifurcation) . The ECA above the bifurcation is coagulated and the two sutures are then cut below the /A^ coagulation. A 25 mm length 4-0 nylon suture, its tip rounded by heating near a fine tipped cauterizer, is introduced into the ECA lumen. 20-22 mm of the suture is inserted into the ECA stump. The suture around the ECA is tightened to hold the occluding suture in place and EEC reading is checked to confirm occlusion by the appearance of a flat line. At this point the intraluminal suture has blocked the origin of the Middle Carotid Artery (MCA) , occluding all sourceε of blood flow from the Interior Carotid Artery (ICA) , the anterior Carotid Artery (ACA) , and the poεterior cerebral artery (PCA) . At 105 min later the εuture iε gently retracted under halothane aneεthesia to allow blood flow back into the middle cerebral artery. The neck incision is cloεed and animals allowed to recover from anesthesia. At 24 hrs animalε are evaluated for behavioral deficitε, εacrificed, transcardial perfused, brains removed and TTC stained for visualization of infarcted region using a computer asεisted syεtem. The application of compound Id iε εhown in the time line diagram. Thirty minuteε prior to induction of ischemia (SUTURE IN) Compound Id in isotonic εaline εolution waε infused for 15 min at a loading dose of 250 μg/kg/min (50 μl/min) followed by maintenance rate of 50 μg/kg/min for the remaining 12 hrs. As εhown below, infusion of compound Id had no apparent effect on a number of physiological parameters such aε blood preεεure, heart rate, body temperature and blood gaεeε. Infuεion of Compound Id did have a significant effect on infarct volume in thiε model of focal iεchemia in the rat. Drug infuεion reduced infarct volume by 52% from 139.+31 (n=7] to 71±28 (n=8) mm 3 (p = 0.05) . Eff f n in Infusi n h m I n ri Example G Effectε on Recovery of Mvocardial Function Following Iεchemia/ Reperfuεion Injury The ability of εeveral AMP deaminaεe inhibitorε of the preεent invention to improve the recovery of left ventricular function following iεchemia/reperfuεion injury was evaluated in rabbits and in swine. Anesthetized, open-chest New Zealand White rabbits were ? used to assess recovery of regional wall function following repeated episodes of regional myocardial ischemia and reperfusion. Fractional segment shortening was used as an index of left ventricular function in a region of the myocardium made ischemic by repeated occlusions of a coronary artery branch. Anesthesia was induced and maintained with pentobarbital sodium. The rabbits were intubated and the lungs were ventilated with room air supplemented with oxygen. The heart waε exposed via a left lateral thoracotomy and suεpended in a pericardial cradle. A εuperficial branch of the left coronary artery waε identified and iεolated with a silk suture. A pair of sonomicrometry cryεtals were inserted into the sub-endocardium in the center of the ischemic zone for measurement of myocardial segment length. A catheter waε inεerted into the left ventricle via a small apical incision for measurement of LV presεure and determination of LV dP/dt. Hemodynamic variableε (LV preεsure and dP/dt, heart rate, and systemic arterial presεure) and fractional εegment shortening were continuously monitored throughout each experiment. A similar protocol was performed in Yucatan minipigs to determine whether compounds of the present invention could also improve myocardial function following ischemia/reperfusion injury in large animals, which have cardiovascular anatomy and physiology more similar to that of humans . In order to simulate the clinical occurrence of regional myocardial dysfunction following an ischemic event, and the ability of the present compoun/Ads to improve functional recovery, a region of the left ventricle was made iεchemic by occluding a large branch of the left coronary artery. Following a εtabilization period, either an AMP deaminaεe inhibitor of the present invention or vehicle was infused for 15 minutes (rabbits) or 30 minutes (pigs) prior to the first occlusion period. In rabbitε, four five-minute occlusions, separated by 5-minute reperfusion periodε, were used to induce myocardial stunning. In pigs, eight minute occlusion/reperfuεion periodε were uεed to produce a εimilar level of ventricular dyεfunction. The infuεion of drug or vehicle waε stopped 30 minutes after release of the final occlusion, and all hemodynamic variables were monitored for an additional 90 minutes (total of 120 minutes reperfusion) to assesε functional recovery. Left ventricular fractional εegment εhortening after 120 minuteε of reperfusion, expresεed as a percent of the values recorded immediately prior to the firεt occluεion, waε uεed to evaluate the utility of compoundε of the preεent invention to improve functional recovery of the heart following an iεchemic inεult. Three compoundε which are highly εelective inhibitorε of AMP deaminaεe (compound lm, compound 1j , and compound Ik) and two compounds which are selective for both AMP deaminaεe and adenoεine deaminase (compound la and compound If) were evaluated in the rabbit model of post-ischemic myocardial dyεfunction. Compoundε lm and If were alεo evaluated in the pig. All of the compounds tested provided highly significant /3 improvement in myocardial function two hours after ischemic insult. None of the compounds caused significant changes in hemodynamics at the doεeε used in these studieε. Effect of AMPDA Inhibitors on Recovery of Left Ventricular Function Following Mvocardial Ischemia A. RABBITS vehicle -- 24±2 If 30 49±6* lm 30 62±9* * = p < 0.05 vs. vehicle control Example H Effects on Arterial Thrombus Development The ability of several AMP deaminase inhibitors of the present invention to prevent development of intra-arterial thrombi was evaluated in three animal models: the rabbit, dog, and the rat. Aneεthetized New Zealand White rabbitε were used to evaluate the effects of the present compounds on thrombus 13/ development in and around a stenoεed artery which has been subjected to intimal injury. This model, most commonly known as the "Folts" thrombosiε model, haε been extenεively deεcribed in the literature. Briefly, a large artery (carotid in the rabbit, left circumflex in the dog) iε isolated, and the endothelium in a small section of the vessel is damaged by carefully crushing the vessel. The vesεel iε then εtenoεed in the same region by placement of a restrictive clip on the outεide of the veεεel. Blood flow through the stenosed veεεel iε then continuouεly monitored. Characteriεtically, blood flow gradually decreaεeε as platelets and other material accumulate at the site of injury/stenoεiε, and then abruptly increaseε as the thrombuε breakε free and iε waεhed downεtream. Another thrombuε then beginε to form, and the cycle repeatε itself with a consistent period. Thus, the primary endpoint of these studies was the frequency of cyclic flow reductions. After a conεiεtent cycle of flow reductionε waε eεtabliεhed, the frequency of cyclic flow reductionε (CFRs) were observed during a 30 minute control period. Infusionε of either vehicle or one of the compoundε of the preεent invention were εtarted. Compoundε were adminiεtered at increasing doεeε (5, 10, and 30 μg/kg/min) at 30 minute intervals or until CFRs ceased. After CFRs were abolished, blood flow waε continuously monitored for 60 minutes in order to be certain that the cycles did not return. The table below showε the compoundε teεted in the rabbit A "Folts" model. All of the compounds tested significantly decreased the frequency and severity of CFRs in all rabbits. None of the compounds produced significant changes in systemic hemodynamics at the doses used for these studies. Three compounds (compound la, compound lm, and compound If) were also evaluated in a similar model in dogs and were found to be not effective or marginally effective at decreasing thrombus formation. The marginal effectivenesε of these compoundε in dogε iε likely attributable to differenceε in the metaboliεm of adenoεine between dogs and most other mammals. Effect Of AMPDA/ADA Inhibitors In Folts Anti-Thrombosis Model Several of the present compounds were also evaluated in a /33 different model of arterial thrombosis which is less dependent on platelets and more dependent on thrombin and other blood clotting mechanisms. Anesthetized Sprague-Dawley ratε were used to evaluate the effectiveness of these compounds on thrombuε formation. An arterial-venouε εhunt waε created by inεerting catheterε into the right common carotid artery and left internal jugular vein. A length of 1-0 silk suture was then inεerted into thiε εhunt for 15 minuteε, after which it was removed and weighed to determine the size of the thrombus which had formed during the 15 minute period. An infusion of either vehicle or one of the present compounds (l-10μg/kg/min) was then εtarted. After 15 minutes of infusion, a second suture was inserted into the shunt for 15 minutes, then removed and weighed. Determination of effectiveness of the compound was made by comparing the wet thrombus weight after infusion to that obtained prior to infusion. If the thrombus weight was significantly decreased after a compound waε infused, this was taken as evidence of antithrombotic activity. A modification of thiε protocol waε also used to asseεε the efficacy of several of these compounds one hour after oral administration. The protocol was similar to that described above, except that thrombus weights from compound-treated animals were compared to the weights obtained from animals treated with a placebo (vehicle) . The table below shows the effects of the present compoundε on thrombuε formation following intravenouε infusion. The second table below shows the effects of several of these compounds following oral administration. Several of the compounds were very effective at decreaεing thrombuε formation when administered intravenously in this model. Three of the compounds (compound Ik, lq and lr) were also effective when administered orally, with an effective oral dose of 10 mg/kg (compounds lq and lr) and 3 mg/kg (compound Ik) . Effects of AMPDA Inhibitor n Thrombuε Formation Oral Activity AMPDA Inhibitors on Thrombus Weiσht / 3 " Compound Oral Doεe (mσ/kσ ) Thrombus Weiσht (mσ ) vehicle 48 ± 2 lc 10 26 ± l * t If 10 41 ± 2 lj 10 42 ± 3 Ik 1 47 ± 1 Ik 3 36 ± 1* Ik 10 27 ± 2 * lm 10 47 ± 2 lq 10 24 ± 2 * t lr 10 22 ± 3 * t = p < 0 . 05 vs control t control thrombus weight 45±1 Example I Effect of AMPDA Inhibitor on Mvocardial Infarct Size Following Ischemia The ability of several AMP deaminase inhibitors of the present invention to decrease myocardial infarct εize following prolonged iεchemia waε evaluated in vitro in iεolated buffer-perfuεed rabbit heartε. Isolated rabbit hearts were cannulated via the ascending aorta, mounted on a Langendorff apparatus and perfuεed at a conεtant preεεure of 80 mm Hg with Krebε-Henseleit buffer (pH 7.4, 37.7 °C) . The hearts were paced at 220 beats/min. A fluid-filled latex balloon waε inεerted into the left ventricle via the left atrium to monitor left ventricular preεεure. Left ventricular end diaεtolic pressure was maintained at 6 to 12 mm Hg. Coronary artery flow was measured gravimetrically. The hearts were allowed 30 minutes to equilibrate before beginning the experiment. Regional ischemia was produced by tying a snare (silk suture) around a large branch of the left coronary artery for 30 minutes. Thiε ischemic period was followed by 120 minutes of reperfusion, after which the hearts were perfused with florescent beads to determine the risk area, dismounted, and frozen. On the following day, the frozen tissue was cut into 2 mm transverεe sections, which were treated with 1% triphenyltetrazolium chloride (TTC) for determination of infarct area. The areas of risk zone and infarct were then determined by planimetry. The area of infarcted tisεue, expressed as a percent of the area at risk (total perfusion bed of the occluded vessel) is the primary endpoint of the study. Two compounds of the present invention (compound If, 1.0 M and compound lm, 0.1-1.0 μM) were studied using this protocol. The compounds (or vehicle) were infused with the perfuεate for 30 minutes prior to ischemia, during ischemia and for 60 minutes after the ischemia. With this protocol, a decrease in the infarct/risk area ratio is taken aε evidence of significant myocardial protection. The effects of compounds If and lm on infarct εize are εummarized in the table below. Both compoundε provided εignificant cardiac protection. The finding that compound lm appearε to provide greater protection at a concentration of 0.1 μM than at 1 μM may be an indication of the "bell-shaped" dose-reεponεe curve 1 "1 which has been consistently demonstrated with adenosine regulating agents in other in vitro models. These doses of lm and If caused slight (7-8%) decreaseε in baseline left ventricular developed pressure, but did not affect coronary blood flow. Effects of AMPDA Inhibitorε on Infarct Size following Prolonσed Myocardial Ischemia Compound Perfusate Infarct Size Concentration (μM) (% Risk Area) vehicle 23.4 ± 1.2 If 1 15.2 ± 4.8* lm 0.1 9.3 ± 1.1* lm 1 16.3 ± 4.1* p < 0.'05 vs. vehicle control

Claims: 3 We claim : 1. A compound of the formula wherein Y is -C(K)- or nitrogen; K iε hydrogen, halogen, azido, or amino; G is hydrogen, lower alkyl, or amino; Z is azido, hydroxy, thio, lower acyloxy, or lower thioacyloxy; Z' is hydrogen or lower alkyl; J is hydrogen or lower alkyl; B iε a εtraight or branched divalent group selected from lower alkylene, lower alkylenylaryl, lower alkylenylamino, lower alkylenylaminoalkylene, lower alkylenylaminoaryl, lower alkylenyloxyaryl, lower alkylenylacylamino, lower alkylenyloxyalkyenylaryl, lower alkylenylacylammoalkylene, lower alkyleneoxy, lower alkoxyalkyl, lower alkylenethio, lower alkylthioalkyl, lower alkynyl or lower alkenyl, alkylcarboxamidoalkyl, alkylcarboxamidoalkylaryl, hydroxylated lower alkylene, halogenated lower alkylene, halogenated lower alkylenylaryl, alkylenetetraz /o3lo 9, alkylene-3H-l, 2, 3 , 5- oxythiodiazolo, alkylenethiazolidine-2-, 4-diono, alkyleneoxazolidin-2, 4-diono or iε a direct link; A is a divalent group selected from a straight or branched alicyclic group, a straight or branched heteroalicyclic group, aryl group or heteroaryl group, all optionally substituted with substituentε independently εelected from lower alkyl, lower aryl, lower aryloxy, aralkyl, perhaloalkoxy, aralkoxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, amino, guanidino, halogen, hydroxy, lower alkoxy, lower alkylthio, carboxyalkyl, carboxyl, carboxamido, carboxamidoalkylaryl, carboxamidoaryl, aminocarboxamidoalkyl, cyano, lower perhaloalkyl, or iε a direct link; X is hydrogen, lower alkyl, lower alkoxy, halogen, hydroxy, acyloxy, thio, amino, azido, cyano, carboxyl, carboxyalkyl, carboxyaryl, carboxyaralkyl, tetrazolo, 3H-1,2,3,5- oxythiodiazolo, thiazolidine-2-, 4-diono, oxazolidin-2, 4-diono, carboxamido, carboxamidoalkyl, carboxamidoaralkyl, carboxamidoaryl, guanidino, -PO3EE' , or C(W)C02E(COQ) ; E and E' are independently selected from hydrogen, lower alkyl, aryl or aralkyl; W is hydrogen, lower alkyl, halogenated lower alkyl, carboxyalkyl, carboxyaralkyl, or halogen; Q is lower alkyl, lower alkoxy, aralkoxy, lower alkylthio, alkylamino, hydroxy, amino, arylamino, aralkylamino or aryloxy; and pharmaceutically acceptable salts thereof; with the proviso that (a) when B is a direct link, then A is not substituted tetrahydrofuran or substituted cyclopentylene; (b) when B is lower alkoxyalkyl and A is a direct link, then X is not hydroxy; and (c) when B is methylene and A iε a direct link, then X is not hydrogen and (d) when B is methylene, X is hydrogen then A is not phenyl, (e) A and B cannot both be direct links. 2. A compound of claim 1 where Y iε -C(-K)-. 3. A compound of claim 2 where K iε hydrogen. 4. A compound of claim 1 where G iε hydrogen or methyl. 5. A compound of claim 1 where Z iε hydroxy or azido and Z' iε hydrogen. 6. A compound of claim 1 where Z iε hydroxy and Z' iε lower alkyl of one to three carbons. 7. A compound of claim 1 where J is hydrogen. 8. A compound of claim 1 where B is straight or branched lower alkylene, lower alkylenylaryl or a direct link. 9. A compound of claim 1 where A is a divalent group selected from a straight or branched alicyclic group, a straight or branched heteroalicyclic group, aryl or heteroaryl, all optionally substituted with substituents independently selected from amino, halogen, hydroxy, cyano, lower alkyl, lower alkoxy, lower aryl, lower aryloxy, aralkyl, aralkoxy, heteroaryl or is a direct link. 10. A compound of claim 1 where X is hydrogen, carboxyl, carboxyalkyl, carboxyaryl, carboxyaralkyl, tetrazolo, 3H- / / 1 , 2 , 3 , 5-oxythiodiazolo , thiazolidine-2 - , 4 -diono , oxazolidin- 2 , 4 -diono , or C (W) C02E (COQ) ; where E and E' are independently εelected from hydrogen, lower alkyl, aryl or aralkyl; W is hydrogen or lower alkyl; Q is lower alkoxy, aralkoxy, aralkylamino, alkylamino, hydroxy, amino, arylamino or aryloxy. 11. A compound of claim 3 where Z is hydroxy or azido and Z' is hydrogen and the carbon to which they are attached is of the R configuration. 12. A compound of claim 3 where Z iε hydroxy or azido, G and Z' are independently hydrogen or methyl and J iε hydrogen. 13. A compound of claim 12 where B iε εtraight or branched lower alkylene, εtraight or branched lower alkylenylaryl, or a direct link. 14. A compound of claim 12 where A is a divalent group selected from a straight or branched alicyclic group; a straight or branched heteroalicyclic group; aryl; or heteroaryl; all optionally substituted with substituents independently selected from amino, halogen, hydroxy, cyano, lower alkyl, lower perhaloalkyl, lower alkoxy, lower aryl, lower aryloxy, aralkyl, aralkoxy, and heteroaryl; or is a direct link. 15. A compound of claim 12 where X is hydrogen, carboxyl, carboxyalkyl, carboxyaryl, carboxyaralkyl, tetrazolo, 3H- 1,2,3, 5-oxythiodiazolo, thiazolidine-2-, 4-diono, oxazolidin- 2,4-diono, or C (W)CO2E(COQ) ; where E and E' are independen /tlΆy- selected from hydrogen, lower alkyl, aryl or aralkyl; W iε hydrogen or lower alkyl; Q is lower alkoxy, aralkoxy, aralkylamino, alkylamino, hydroxy, amino, arylamino or aryloxy. 16. A compound of claim 12 where B is straight or branched lower alkylene, straight or branched lower alkylenylaryl, or a direct link; A is a divalent group selected from a straight or branched alicyclic group; a straight or branched heteroalicyclic group; aryl; or heteroaryl; all optionally substituted with subεtituentε independently εelected from amino, halogen, hydroxy, cyano, lower alkyl, lower perhaloalkyl, lower alkoxy, lower aryl, lower aryloxy, aralkyl, aralkoxy, and heteroaryl; or iε a direct link; X iε hydrogen, carboxyl, carboxyalkyl, carboxyaryl, carboxyaralkyl, tetrazolo, 3H-1,2,3 , 5-oxythiodiazolo, thiazolidine-2-, 4-diono, oxazolidin-2 , 4-diono, or C(W)C02E(COQ) ; where E and E' are independently εelected from hydrogen, lower alkyl, aryl or aralkyl; W is hydrogen or lower alkyl; Q is lower alkoxy, aralkoxy, aralkylamino, alkylamino, hydroxy, amino, arylamino or aryloxy. 17. A compound of claim 16 where X is hydrogen and A iε a direct link. 18. A compound of claim 16 where X is hydrogen and A is aryl. *3 19. A compound of claim 16 where X is hydrogen and A is alicyclic. 20. A compound of claim 16 where A is a direct link and X is carboxyl, carboxyalkyl, carboxyaryl, carboxyaralkyl, tetrazolo, 3H-1, 2, 3 , 5-oxythiodiazolo, thiazolidine-2-, 4-diono, oxazolidin-2 , 4-diono. 21. A compound of claim 16 where A is a direct link, and X iε C (W)C02E(COQ) where E and E' are independently selected from hydrogen, lower alkyl, aryl or aralkyl; W is hydrogen or lower alkyl; Q is lower alkoxy, aralkoxy, alkylamino, hydroxy, amino, arylamino, aralkylamino or aryloxy. 22. A compound of claim 16 where A is not a direct link and X is carboxyl, carboxyalkyl, carboxyaryl, carboxyaralkyl, tetrazolo, 3H-1, 2, 3 , 5-oxythiodiazolo, thiazolidine-2-, 4-diono, oxazolidin-2 , 4-diono. 23. A compound of claim 16 where B is methylene, A is 1,2- [6, 6-dimethyl [3.1.1]bicyclohept-2-methylene] and X is hydrogen. 24. A compound of claim 16 where A is cycloheptylene, B iε a direct link and X iε hydrogen. 25. A compound of claim 16 where B iε -(CH2)4~. A is a direct link, X is -C (W)CO2E(COQ) where W iε hydrogen or methyl, E is aralkyl and Q is hydroxy. 26. A compound of claim 16 where B is -(CH2)4~, A is a direct link, X is -C (W)CO2E(COQ) where W is hydrogen or methyl, E is hydroxy, and Q is aralkylamino. 27. A compound of claim 16 where B is 1, 7- [3 , 7-dimethyloct-6- enylene] , A is a direct link and X is hydrogen. 28. A compound of claim 16 where B is lower alkylene of two to seven carbons and A is aryl. 29. A compound of claim 28 where B is lower alkyl of one to five carbons and A is phenylene. 30. A compound of claim 29 where A is 1,2-phenylene and X is methyl. 31. A compound of claim 29 where A is 1, 4-phenylene and X is propoxy. 32. A compound of claim 16 where B is -(CH2)2~< and A is 1,3- arylene and X is carboxyl. 33. A compound of claim 16 where B iε -(CH2)2 _ and. A is optionally substituted naphthalene. 34. A compound of claim 16 where B is -(CH2)2- * ~ - is l,3-(2- methyl)phenylene and X is carboxyl. 35. A compound of claim 16 where B is -(CH2)2-' A is 1,3- naphthylene and X iε carboxyl . 36. A compound of claim 16 where B is -(CH2)2~» A i 1,3- (5- bromo)phenylene and X is carboxyl. 37. A compound of claim 16 where B is -(CH2)2~» A is 2,4- thienyl and X is carboxyl. 38. A compound of claim 16 where B is 1, 5- (6-arylhexylene) and X is carboxyl. 39. A compound of claim 16 where B is 1, 5- (6-phenylhexylene) and X is carboxyl. 40. A compound of claim 16 where B is 1,5- (6- (3- J 5 " bromophenyl)hexylene) and X is carboxyl. 41. A compound of claim 16 where B is alkyl of four to ten carbons, A is a direct link and X is hydrogen. 42. A compound of claim 16 where B is heptyl, A is a direct link and X is hydrogen. 43. A method of treating or preventing thrombosis in a mammal comprising administering a therapeutically effective amount of a compound which inhibits adenosine monophosphate deaminase. 44. A method of reducing infarct size in a mammal comprising administering of a therapeutically effective amount of a compound which inhibitε adenosine monophosphate deaminase. 45. A method of treating or preventing angina in a mammal comprising administering a therapeutically effective amount of a compound which inhibits adenosine monophosphate deaminase. 46. A method of treating unstable angina in a mammal comprising administering a therapeutically effective amount of a compound which inhibits adenosine monophosphate deaminase. 47. A method of treating or preventing seizures in a mammal comprising adminiεtering a therapeutically effective amount of a compound which inhibits adenosine monophosphate deaminase. 48. A method of treating or preventing pain in a mammal comprising administering a therapeutically effective amount of a compound which inhibits adenosine monophoεphate deaminase. 49. A method of treating or preventing inflammation in a mammal comprising adminiεtering a therapeutically effective amount of a compound which inhibitε adenoεine monophoεphate deaminaεe. /Yά 50. A method of treating arthritis in a mammal comprising administering a therapeutically effective amount of a compound which inhibits adenosine monophosphate deaminase. 51. A method of treating or preventing sepsis in a mammal comprising administering a therapeutically effective amount of a compound which inhibits adenosine monophosphate deaminase. 53. A method of treating or preventing malaria in a mammal comprising administering a therapeutically effective amount of a compound which inhibits adenosine monophoεphate deaminaεe or adenosine monophosphate deaminase and adenosine deaminase. 54. A method of treating or preventing ischemia in a mammal comprising administering a therapeutically effective amount of a compound which inhibitε adenoεine monophosphate deaminase. 55. A method of treating or preventing iεchemia in a mammal compriεing adminiεtering a therapeutically effective amount of a compound which iε able to penetrate the cell membrane and which inhibitε adenosine monophosphate deaminase as defined by an enzyme asεay uεing purified or εemi-purified enzyme extractε. 56. A method of treating or preventing iεchemia in a mammal compriεing adminiεtering a therapeutically effective amount of a compound or prodrug thereof which inhibitε adenoεine monophoεphate deaminaεe wherein εaid compound inhibitε said enzyme with a Ki of lesε then or equal to about 10 μM. 59. A method of treating or preventing ischemia in a mammal comprising administering a therapeutically effective amount of a compound or prodrug thereof which inhibits adenosine IV? monophoεphate deaminaεe wherein the orally active dose of said compound iε leεs than or equal to about 10 mg/kg. 60. A method of treating or preventing ischemia in a mammal comprising administering a therapeutically effective amount of a compound which inhibits adenosine monophosphate deaminase without requiring phosphorylation or phosphoribosylation. 61. A method of treating or preventing thrombosiε in a mammal comprising administering a therapeutically effective amount of a compound or prodrug thereof which inhibits adenosine monophosphate deaminase wherein said compound inhibits said enzyme with a Ki of less than or equal to 10 μM. 62. A method of treating or preventing thrombosiε in a mammal compriεing adminiεtering a therapeutically effective amount of a compound which inhibitε adenoεine monophosphate deaminase without requiring phosphorylation or phosphoriboεylation. 63. A method of treating or preventing thromboεiε in a mammal compriεing administering a therapeutically effective amount of a compound or prodrug thereof which inhibits adenosine monophosphate deaminase wherein the orally active dose of said compound is leεε than or equal to about 10 mg/kg. 64. A method of treating or preventing thromboεis in a mammal comprising administering a therapeutically effective amount of a compound which is able to penetrate the cell membrane and which inhibits adenosine monophosphate deaminase as defined by an enzyme assay using purified or semi-purified enzyme extracts. 65. A method of treating a mammal comprising administering a therapeutically effective amount of a compound which inhibits adenosine monophosphate deaminase as defined by an enzyme asεay uεing purified or εemi-purified enzyme extractε and which is able to penetrate the cell membrane. 66. A method of treating a mammal comprising administering a therapeutically effective amount of a compound or prodrug thereof which inhibitε adenosine monophosphate deaminase wherein said compound inhibits said enzyme with a Ki of less then or equal to about 10 μM. 67. A method of treating a mammal comprising administering a therapeutically effective amount of a compound or prodrug thereof which inhibits adenoεine monophoεphate deaminase wherein the orally active dose of said compound is leεs than or equal to about 10 mg/kg. 68. A method of treating a mammal comprising adminiεtering a therapeutically effective amount of a compound which inhibitε adenoεine monophosphate deaminase without requiring phosphorylation or phosphoriboεylation.

Inventors: BOOKSER BRETT CARDER, ERION MARK DAVID, GRUBER HARRY EDWARD, KASIBHATLA SRINIVAS RAO, BOOKSER, BRETT, CARDER, ERION, MARK, DAVID, GRUBER, HARRY, EDWARD, KASIBHATLA, SRINIVAS, RAO
Applicants: GENSIA INC, GENSIA, INC.
Application year: 1994
Main classification: C07D487
IPC codes: A61K31, A61P7, A61P9, A61P25, A61P29, A61P43, C07D487